<PAGE>

                                                                    EXHIBIT 10.1

(ARCHEMIX LOGO)

                              EMPLOYMENT AGREEMENT

     This Employment Agreement (the "Agreement"), is made and entered into this
7th day of March 2003, by and between Archemix Corp. (which, together with any
parent companies, subsidiaries, affiliates, successors and assigns shall be
referred to as "Archemix" or the "Company"), with its principal offices located
at One Hampshire Street, Cambridge, MA 02139, and Dr. Errol De Souza (the
"Executive").

                                   WITNESSETH

     WHEREAS, the Company has a need for the Executive's personal services in an
executive capacity; and

     WHEREAS, the Executive and the Company desire to enter into a formal
Employment Agreement to fully recognize the anticipated contributions of the
Executive to the Company and to assure continuous, harmonious conduct of the
Company's business.

     NOW, THEREFORE, in consideration of the mutual promises, terms, provisions,
and conditions contained herein and for other good and valuable consideration,
the receipt and sufficiency of which are hereby mutually acknowledged, the
parties agree as follows:

1.   Positions; Responsibilities.

     (a) Subject to the terms and conditions of this Agreement, the Company will
employ the Executive, and the Executive will be employed by the Company as
President and Chief Executive Officer ("CEO"). The Executive's responsibilities
shall include any responsibilities normally associated with such positions and
any other responsibilities assigned reasonably by the Board of Directors (the
"Board"). During the period while the Executive is employed hereunder, the
Company will ensure that the Executive is nominated, and use its best efforts to
cause the Executive to be elected, to serve as a Director of the Company. The
Executive will be deemed to have resigned from the Board and from any other
position or role related to the Company on the date the Executive's employment
with the Company ends.

     (b) Devotion to Duties. Except for vacations and absences due to temporary
illness in accordance with the policies of the Company, while the Executive is
employed hereunder, the Executive will use best efforts to perform faithfully
all duties assigned to the Executive pursuant to this Agreement and to devote
the Executive's full business time and energies to the business and affairs of
the Company, provided, however, that the Executive may, with the prior written
consent of the Board, engage in other business activities which do not conflict
with the Executive's duties hereunder, whether or not such activity is pursued
for gain, profit or other pecuniary advantage. While the Executive is employed
hereunder, the Executive will not serve as an employee, consultant, director or
advisor to any person or entity without the prior written consent of

 ARCHEMIX CORPORATION  One Hampshire Street, 5th floor  Cambridge, MA 02139 USA
                                www.archemix.com
<PAGE>

the Company; provided, however, that the Executive shall be allowed, to the
extent such activities do not substantially interfere with the performance by
the Executive of his duties and responsibilities hereunder, to (a) manage the
Executive's personal, financial and legal affairs, and (b) serve on the
corporate, civic or charitable boards or committees set forth on Schedule A
hereto.

     The Executive and the Company acknowledge that the Company desires that
Executive relocate to the Boston area and the Executive intends to relocate with
his spouse and family from Basking Ridge, New Jersey to the Boston area within a
reasonable period of the Commencement Date or such extended time that Executive
and the Company may mutually and reasonably agree.

2.   Term of Employment.

     (a) Term; Termination. Subject to the terms hereof, the Executive's
employment hereunder will commence on or before April 1, 2003 (the "Commencement
Date") and will continue until the fifth anniversary of such Commencement Date
(the "Initial Term"), provided that on the fifth anniversary of the Commencement
Date and each anniversary thereafter, the term of the Executive's employment
hereunder will be automatically extended for an additional period of one (1)
year (each a "Subsequent Term") unless either the Executive or the Company has
given written notice to the other that such automatic extension will not occur
(a "Non-Renewal Notice"), which notice was given not less than ninety (90) days
prior to the relevant anniversary of the Commencement Date. Notwithstanding the
foregoing the Executive's employment hereunder will terminate upon the first to
occur of the following (each of which is referred to as a "Termination of
Employment"):

          (i)  the Executive's death;

          (ii) by the Company:

               (A) by written notice to the Executive, following the Executive's
failure due to illness, accident or any other physical or mental incapacity to
perform the essential functions of the Executive's positions for ninety (90)
consecutive days or an aggregate of one hundred and twenty (120) days within any
period of three hundred and sixty-five (365) consecutive days during the term
hereof ("Disability");

               (B) for Cause; or

               (C) without Cause

          (iii) By the Executive:

               (A) with Good Reason;

               (B) without Good Reason

For purposes of this Agreement, the Company or the Executive may initiate a
Termination of Employment in any manner permitted hereunder by giving the other
party written notice thereof ("Termination Notice"). The effective date (the
"Termination Date") of any Termination of Employment shall be deemed to be the
later of (i) the date on which the Termination Notice is given and (ii) the date
specified as the effective date in the Termination Notice; provided,


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however, that in the case of the Executive's death, the Termination Date shall
be the date of death and in the case of a Disability Termination, the
Termination Date shall be the thirtieth (30th) day after receipt by the
Executive or the Company of the Termination Notice stating that the termination
is a Disability Termination.

     (b) Definition of "Cause". For purposes of this Agreement, "Cause" means
any of the following:

          (i)  a continuing failure by the Executive to render services to the
               Company in accordance with the Executive's assigned duties (other
               than such a failure as a result of Disability;

          (ii) any act or omission by the Executive involving willful misconduct
               or gross negligence which results in material harm to the
               Company;

          (iii) the Executive's commission of any felony or any fraud, financial
               wrongdoing, willful disloyalty, deliberate dishonesty or breach
               of fiduciary duty in connection with the performance of the
               Executive's obligations to the Company AND which materially and
               adversely affects the business activities, reputation, or
               goodwill of the Company;

          (iv) the Executive's deliberate disregard of a Company rule or policy
               which materially and adversely affects the business activities,
               reputation, or goodwill of the Company, or,

          (vi) the Executive's material breach of this Agreement.

In the event of a termination for Cause, the Termination Notice given to the
Executive by the Company shall state that the Termination of Employment is "for
Cause." Such written notice shall specify the particular act or acts, or failure
to act, which is or are the basis for the decision to so terminate the
Executive's employment for Cause. The Executive shall be given the opportunity
within 30 calendar days of the receipt of such notice to meet with the Board to
defend such act or acts, or failure to act, and the Executive shall be given 15
days after such meeting to cure such act (or failure to act) to the Board's
reasonable satisfaction. Upon failure of the Executive, within such latter 15
day period, to so cure such act or failure to act, the Executive's employment by
the Company shall be deemed terminated for Cause. All other terminations
initiated by the Company (other than due to Disability) shall be referred to as
termination without Cause.

     (c) Definition of "Good Reason", For purposes of this Agreement, any
Termination of Employment initiated by the Executive within 90 days following
the occurrence, without the Executive's prior written consent, of any of the
following events shall be a termination with Good Reason and the Company shall
be given at least thirty days prior written notice of any such Termination with
Good Reason, and the Company shall have 15 days after such notice to cure such
occurrence:

          (i) The appointment of a President or CEO other than the Executive to
serve in such position(s) during the term hereof without the Executive's
consent;


                                        3
<PAGE>

          (ii) Any material reduction in the Executive's responsibilities or
authority within the Company, including, without limitation, a change in the
lines of reporting such that the Executive no longer reports to the Board;

          (iii) A reduction in the Executive's compensation except such a
reduction in connection with a reduction in compensation of other Company
executives at the level of senior management or with the Executive's consent;

          (iv) A material breach of this Agreement by the Company;

          (v) Any failure by the Company to have this Agreement explicitly
assumed by a successor;

          (vi) Any material reduction in the Executive's welfare benefits in the
aggregate (other than any across the board reduction imposed on substantially
all other members of the Company's senior management); or

          (vii) Any relocation of the Executive's principal office location to a
location more than 35 miles from the Boston metropolitan area.

     All other terminations initiated by the Executive shall be considered
termination without Good Reason.

3. Compensation.

     (a) Base Salary. During the period that the Executive is employed by the
Company, the Company will pay the Executive a base salary at the annualized rate
of not less than $400,000, less customary deductions for taxes, benefit
contributions and the like (the "Base Salary"). The Base Salary for 2004 and
each calendar year thereafter will be reviewed for increases, but not decreases,
by the Board no later November 30 of each year throughout the Executive's
employment with the Company. The Base Salary will be payable in substantially
equal installments in accordance with the Company's payroll practices as in
effect from time to time. For purposes of this Agreement, such base salary, as
the same may be increased as aforesaid, is referred to herein as the "Base
Salary."

     (b) Bonus. In addition to the Base Salary, the Executive shall be eligible
to receive an annual bonus for each calendar year that the Executive completes
with the Company, payable within ninety (90) days following the completion of
the relevant year (the "Annual Bonus"). The award and amount of any Annual Bonus
shall be determined by and in the sole discretion of the Board or its
designee(s), with a target amount equal to forty percent (40%), pro-rated for
the partial year 2003, of the Base Salary earned during the year to which the
Annual Bonus relates. The criteria for the award of any Annual Bonus shall be
agreed upon by the Executive and the Board or its designee(s) within thirty (30)
days following the Commencement Date for 2003 (and by January 31 of each
subsequent calendar year that the Executive remains employed by the Company),
and shall be based fifty percent (50%) on Company-wide performance and fifty
percent (50%) on the Executive's individual performance. If all of the criteria
for the award of any Annual Bonus are exceeded in any calendar year, the Board,
in its sole discretion may award an amount that exceeds forty percent (40%).
Notwithstanding the above, for calendar year 2003 only, the Executive shall be
entitled to receive, if the Executive has not voluntarily resigned (or given
notice thereof) prior to January 1, 2004, a minimum guaranteed Annual Bonus for
2003 equal to $160,000, multiplied by a


                                        4

<PAGE>

fraction, the numerator of which is the number of days the Executive is employed
by the Company after the Commencement Date and prior to January 1, 2004, and the
denominator of which is 365. The Executive shall also be entitled to a
Commencement Bonus, payable on, or as soon as practicable following, the
Executive's first day of employment pursuant to this Agreement, in the amount of
$50,000, less customary deductions for taxes and benefit contributions.

     (c) Equity Compensation. Subject to approval by the Board, which shall not
be unreasonably withheld or delayed, and as soon as practicable following the
Commencement Agreement, and pursuant to a written stock option agreement (the
"Stock Option Agreement") entered into between the Company and the Executive
under the Company's 2001 Employee, Director and Consultant Stock Plan (the
"Plan") the Executive will be granted an option (the "Option") to purchase
4,250,000 shares of the Company's Common Stock. The exercise price for the
Option will be the fair market value of the Common Stock on the date the Option
is granted and subject to the other terms and conditions of the Option as set
forth in the Plan and the Stock Option Agreement. The Option will be an
incentive stock option to the extent permissible under applicable law, with
(except as provided herein) the Option vesting with respect to twenty-five
percent (25%) of such shares vesting on the first anniversary of the
Commencement Date and the Option with respect to the remaining shares vesting in
twelve (12) equal increments on a quarterly basis over the course of the
subsequent three (3) year period. Notwithstanding anything in this Agreement to
the contrary, upon a "Change in Control" (as such term is defined in the Stock
Option Agreement), all unvested portions of the Option shall be immediately
vested. In addition to the Option described above, the Executive shall be
considered for additional grants of stock options on an annual basis, the number
of which shall be determined by the Board in its sole discretion;

     (d) Vacation. The Executive will be entitled to paid vacation in each
calendar year and paid holidays and personal days in accordance with the
Company's policies for its senior executives as in effect from time to time.

     (e) Fringe Benefits. The Executive will be entitled to participate in any
employee benefit plans which the Company provides or may establish for the
benefit of its senior executives generally (including, but not limited to, group
life, disability, medical, dental and other insurance, retirement, pension,
profit-sharing and similar plans) (collectively, the "Fringe Benefits"),
provided that the Fringe Benefits will not include any stock option or similar
plans relating to the grant of equity securities of the Company except as
provided herein. The Executive's eligibility to participate in the Fringe
Benefits and receive benefits thereunder will be subject to the plan documents
governing such Fringe Benefits. Nothing contained herein will require the
Company to establish or maintain Fringe Benefits

     (f) Relocation Expenses. Upon submission of reasonably detailed invoices,
the Company will pay or reimburse the Executive up to a total of $220,000 (on an
after-tax basis) for all reasonable out-of-pocket expenses incurred by the
Executive in connection with the Executive's (and his spouse and dependent
children) relocation from Basking Ridge, New Jersey to the Boston area,
including, but not limited to, reimbursements for real estate fees and closing
costs on the sale of the Executive's current primary residence, closing costs
and up to 2 points on a mortgage loan on the purchase of a primary residence in
the Boston area, up to six (6) months of temporary housing costs, direct moving
costs including vehicle transfer fees and property storage costs if required,
and up to three (3) house hunting trips to the Boston area for the Executive and
his family.


                                        5

<PAGE>

     (g) Reimbursement of Expenses. In addition to the reimbursements described
above, during the term of this Agreement, the Company shall reimburse the
Executive, in accordance with the policies and practices of the Company in
effect from time to time during such term, for all reasonable and necessary
traveling expenses and other disbursement incurred by the Executive for or on
behalf of the Company in connection with the performance of the Executive's
duties hereunder upon presentation by the Executive to the Company of
appropriate documentation therefore. In addition, upon submission of reasonably
detailed invoices, the Company will pay or reimburse the Executive for up to
$10,000 (on an after-tax basis) for financial planning services each year that
the Executive is employed pursuant to this Agreement.


                                        6
<PAGE>

4. Severance Compensation.

     (a) In the event of any termination of the Executive's employment hereunder
for any reason or for no reason, the Company (i) will pay to the Executive (or
to the Executive's estate) (A) the portion of the Executive's Base Salary that
has accrued prior to such termination and has not yet been paid and (B) an
amount equal to the value of the Executive's accrued unused vacation days, and
(ii) will reimburse the Executive (or the Executive's estate) for expenses
properly incurred and documented by the Executive on behalf of the Company prior
to such termination in accordance with Company policy (collectively, the
"Accrued Obligations"). Such amounts will be paid within 10 days in cash in lump
sum after Termination of Employment.

     (b) Prior to a Change in Control, if the Executive's employment is
terminated by the Company without Cause or by the Executive with Good Reason,
the Company will pay to the Executive: (1) the Accrued Obligations; (2) an
amount equal to twelve (12) months' of Base Salary (provided that Executive
executes and submits a general release of all claims against the Company
(including its officers, directors, employees and affiliates) in a form provided
by the Company (a "General Release") and substantially attached hereto); (3) a
pro-rata Annual Bonus with the respect to the year in which the Termination of
Employment occurred, calculated by multiplying the target Annual Bonus by a
fraction, the numerator of which shall be the number of days worked in the
current calendar year of the Termination of Employment and the denominator of
which shall be 365. Each of the payments specified in (1), (2) and (3), above,
shall be paid in cash in lump sum within 30 days of the Termination of
Employment. In addition, the Company will continue to provide the Executive with
group health insurance and continue to pay the amount of the premium as in
effect on the date of such termination for a period of twelve (12) months
commencing on the effective date of such termination, subject to applicable law
and the terms of the respective policies. The foregoing will not be construed to
extend any period of continuation coverage (e.g., COBRA) required by law.
Furthermore, any unvested portion of the Option will immediately vest with
respect to an additional number of shares that would have vested over the
twenty-four (24) month period following the Termination of Employment.

     (c) Upon or subsequent to a Change in Control, if the Executive's
employment is terminated by the Company without Cause or by the Executive with
Good Reason, and provided that the Executive executes and submits a General
Release, the Company will owe the Executive all rights described in Section
4(b), above, except that the Option shall immediately become fully vested.

     (d) In the event of the termination of the Executive's employment hereunder
either by the Executive without Good Reason, or by Company for Cause, the
Company will pay the Accrued Obligations to the Executive.

     (e)  In the event of the termination of the Executive's employment due to
Disability or death, the Executive (or his estate or representatives) shall be
entitled to receive all Accrued Obligations and in exchange for the Executive's
or his representative's execution and submission of a General Release, pro-rated
target Annual Bonus as calculated in Section 4(b), above. In addition, the
unvested portion of the Option will immediately vest with respect to an
additional number of shares that would have vested over the twelve (12) month
period following the Termination of Employment.

5. Non-Competition, Confidentiality and Inventions.


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<PAGE>

     The Non-Competition, Confidentiality and Inventions Agreement attached as
Exhibit A hereto is incorporated herein and shall be executed by the Executive
and submitted to the Company upon execution of this Agreement.

6. Disclosure of the Executive's Post-Employment Obligations to the Company. The
Executive will provide, and the Company, in its discretion, may similarly
provide, a copy of the Non-Competition, Confidentiality and Inventions Agreement
to any business or enterprise which the Executive may directly or indirectly,
own, manage, operate, finance, join, control or in which the Executive may
participate in the ownership, management, operation, financing, or control, or
with which the Executive may be connected as an officer, director, employee,
partner, principal, agent, representative, consultant or otherwise.

7. Records. Upon termination of the Executive's employment hereunder and at any
other time requested by the Company, the Executive will deliver to the Company
any Company property in the Executive's possession or control, including
products, materials, memoranda, electronic files, notes, records, reports or
other documents or photocopies of the same.

8. Representations. The Executive hereby represents and warrants to the Company
that the Executive understands this Agreement, that the Executive has entered
into this Agreement voluntarily and that the Executive has no commitments or
obligations inconsistent with this Agreement. The Executive agrees to indemnify
and hold the Company harmless against loss, damage, liability or expense arising
from any claim based upon circumstances alleged to be inconsistent with such
representations and warranties.

9. General.

     (a) Notices. All notices, requests, consents and other communications
hereunder will be in writing, will be addressed to the receiving party's
then-current address and will be either (i) delivered by hand, (ii) sent by
overnight courier, or (iii) sent by registered or certified mail, return receipt
requested, postage prepaid. All notices, requests, consents and other
communications hereunder will be deemed to have been given either (i) if by
hand, at the time of the delivery thereof to the receiving party at the address
of such party set forth above, (ii) if sent by overnight courier, on the next
business day following the day such notice is delivered to the courier service,
or (iii) if sent by registered or certified mail, on the fifth business day
following the day such mailing is made. Any notice from the Executive to the
Company must be explicitly directed to the attention of the Board.

     (b) Entire Agreement. This Agreement, together with the other agreements
specifically referred to herein, embodies the entire agreement and understanding
between the parties hereto and supersedes all prior oral or written agreements
and understandings. No statement, representation, warranty, covenant or
agreement of any kind not expressly set forth in this Agreement will affect, or
be used to interpret, change or restrict, the express terms and provisions of
this Agreement.

     (c) Modifications and Amendments. The terms and provisions of this
Agreement may be modified or amended only by written agreement executed by the
parties hereto.

     (d) Waivers and Consents. The terms and provisions of this Agreement may be
waived, or consent for the departure therefrom granted, only by written document
executed by the party entitled to the benefits of such terms or provisions. No
such waiver or consent will be deemed to be or will constitute a waiver or
consent with respect to any other terms or provisions


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<PAGE>

of this Agreement, whether or not similar. Each such waiver or consent will be
effective only in the specific instance and for the purpose for which it was
given, and will not constitute a continuing waiver or consent.

     (e) Assignment. The Company may assign its rights and obligations hereunder
to any person or entity that succeeds to all or substantially all of the
Company's business or that aspect of the Company's business in which the
Executive is substantially involved. The Executive may not assign any rights and
obligations under this Agreement without the prior written consent of the
Company.

     (f) Benefit. All statements, representations, warranties, covenants and
agreements in this Agreement will be binding on the parties hereto and will
inure to the benefit of the respective successors and permitted assigns of each
party hereto. Nothing in this Agreement will be construed to create any rights
or obligations except between the Company and the Executive, and no person or
entity will be regarded as a third-party beneficiary of this Agreement.

     (g) Governing Law. This Agreement and the rights and obligations of the
parties hereunder will be construed in accordance with and governed by the law
of the Commonwealth of Massachusetts, without giving effect to the conflict of
law principles thereof.

     (h) Jurisdiction, Venue and Service of Process. Any legal action or
proceeding with respect to this Agreement that is not subject to arbitration
pursuant to Section 12(i) below must be brought in a court of competent
jurisdiction in Massachusetts. By execution and delivery of this Agreement, each
of the parties hereto accepts for itself and in respect of its property,
generally and unconditionally, the exclusive jurisdiction of the aforesaid
courts.

     (i) Arbitration. Any controversy, dispute or claim arising out of or in
connection with this Agreement, other than a controversy, dispute or claim
arising under Section 5 hereof, will be settled by final and binding arbitration
to be conducted in Boston, Massachusetts pursuant to the national rules for the
resolution of commercial disputes of the American Arbitration Association then
in effect. The decision or award in any such arbitration will be final and
binding upon the parties and judgment upon such decision or award may be entered
in any court of competent jurisdiction or application may be made to any such
court for judicial acceptance of such decision or award and an order of
enforcement.

     (j) Legal Fees and Other Expenses. In the event that a claim for payment or
benefits under this Agreement is disputed, the Executive shall be reimbursed for
all attorney fees and expenses incurred by the Employee in pursing any such
claim, provided that the Executive substantially prevails in respect of the
disputed claim by reason of litigation, arbitration or settlement. In addition,
the Executive shall be paid or reimbursed for all reasonable legal fees and
expenses incurred by the Executive in connection with the review, preparation
and negotiation of this Agreement.

     (k) Severability. The parties intend this Agreement to be enforced as
written. However, (i) if any portion or provision of this Agreement is to any
extent declared illegal or unenforceable by a duly- authorized court having
jurisdiction, then the remainder of this Agreement, or the application of such
portion or provision in circumstances other than those as to which it is so
declared illegal or unenforceable, will not be affected thereby, and each
portion and provision of this Agreement will be valid and enforceable to the
fullest extent permitted by law and (ii) if any provision, or part thereof, is
held to be unenforceable because of the duration


                                        9
<PAGE>

of such provision, the geographic area covered thereby, or other aspect of scope
of such provision, the court making such determination will have the power to
reduce the duration, geographic area of such provision, or other aspect of scope
of such provision, and/or to delete specific words and phrases
("blue-penciling"), and in its reduced or blue-penciled form such provision will
then be enforceable and will be enforced.

     (l) Headings and Captions. The headings and captions used in this Agreement
are for ease of reference only and in no way modify, or affect the meaning or
construction of any of the terms or provisions hereof.

     (m) Injunctive Relief. The Executive hereby expressly acknowledges that any
breach or threatened breach of any of the terms and/or conditions set forth in
Section 5 of this Agreement will result in substantial, continuing and
irreparable injury to the Company. Therefore, in addition to any other remedy
that may be available to the Company, the Company will be entitled to injunctive
or other equitable relief by a court of appropriate jurisdiction in the event of
any breach or threatened breach of the terms of Section 5 of this Agreement.

     (n) No Waiver of Rights, Powers and Remedies. No failure or delay by a
party hereto in exercising any right, power or remedy under this Agreement, and
no course of dealing between the parties hereto, will operate as a waiver of any
such right, power or remedy of the party. No single or partial exercise of any
right, power or remedy under this Agreement by a party hereto, nor any
abandonment or discontinuance of steps to enforce any such right, power or
remedy, will preclude such party from any other or further exercise thereof or
the exercise of any other right, power or remedy hereunder. The election of any
remedy by a party hereto will not constitute a waiver of the right of such party
to pursue other available remedies. No notice to or demand on a party not
expressly required under this Agreement will entitle the party receiving such
notice or demand to any other or further notice or demand in similar or other
circumstances or constitute a waiver of the rights of the party giving such
notice or demand to any other or further action in any circumstances without
such notice or demand.

     (o) Counterparts. This Agreement may be executed in one or more
counterparts, and by the parties hereto on separate counterparts, each of which
will be deemed an original, but all of which together will constitute one and
the same instrument.

     (p) Opportunity to Review. The Executive hereby acknowledges that he has
had adequate opportunity to review these terms and conditions and to reflect
upon and consider the terms and conditions of this Agreement, and that the
Executive has had the opportunity to consult with counsel of his own choosing
regarding such terms. Consequently, the language of any provision hereof shall
not be construed against any party by virtue of the fact that such party drafted
part or all of the Agreement. The Executive further acknowledges that he fully
understands the terms of this Agreement and has voluntarily executed this
Agreement.

                   REMAINDER OF PAGE INTENTIONALLY LEFT BLANK


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<PAGE>

     IN WITNESS WHEREOF, the undersigned have duly-executed this Agreement as of
the day and year set forth below.

EXECUTIVE                               ARCHEMIX CORP.


/s/ Errol De Souza                      By: /s/ Martin Stanton
-------------------------------------       ------------------------------------
Dr. Errol De Souza                          Martin Stanton, President

Attachments:

Exhibit A: Non-competition, Confidentiality and Inventions Agreement

Exhibit B: Form of General Release

Schedule A: List of Outside Activitites


                                       11
<PAGE>

                                                                       Exhibit A

            NON-COMPETITION, CONFIDENTIALITY AND INVENTIONS AGREEMENT

                                 ARCHEMIX CORP.
                              One Hampshire Street
                               Cambridge, MA 02139

                                                               March _____, 2003

Dr. Errol De Souza
[address]

Dear Dr. De Souza:

     This letter is to confirm our understanding with respect to (i) your
agreement not to compete with Archemix Corp. or its parent, subsidiaries or
affiliates (the "Company"), and (ii) your agreement to protect and preserve
information and property which is confidential and proprietary to the Company
(the terms and conditions agreed to in this letter shall hereinafter be referred
to as the "Agreement"). In consideration of the mutual promises and covenants
contained in this Agreement, and for other good and valuable consideration, the
receipt and sufficiency of which are hereby mutually acknowledged, we have
agreed as follows:

     1. Prohibited Competition.

          (a) Certain Acknowledgements and Agreements.

               (i) We have discussed, and you recognize and acknowledge the
competitive and sometimes proprietary aspects of the business of the Company.

               (ii) You acknowledge and agree that a business will be deemed
competitive with the Company if it is developing or performs any of the
services, or is developing or manufactures or sells any of the products provided
or offered or proposed to be provided or offered by the Company or if it
performs or is developing any other services and/or engages in the development,
production, manufacture, distribution or sale of any product similar to services
performed or products produced, manufactured, distributed, sold or being
developed by the Company during the term of your relationship with the Company.

               (iii) You further acknowledge and agree that, during the course
of your performing services for the Company, the Company will furnish, disclose
or make available to you confidential and proprietary information related to the
Company's business and that the Company may provide you with unique and
specialized training. You also acknowledge that such confidential information
and such training have been developed and will be developed by the Company
through the expenditure by the Company of substantial time, effort and money and
that all such confidential information and training could be used by you to
compete with the Company.

<PAGE>

          (b) Covenants Not to Compete. During the period in which you perform
services for or at the request of the Company (the "Term") and for a period of
one (1) year following the expiration or termination of the Term, whether such
termination is voluntary or involuntary, you shall not, without the prior
written consent of the Company:

               (i) for yourself or on behalf of any other person or entity,
directly or indirectly, either as principal, agent, stockholder, employee,
consultant, representative or in any other capacity, own, manage, operate or
control, or be concerned, connected or employed by, or otherwise associate in
any manner with, engage in or have a financial interest in any business which is
directly or indirectly competitive with the business of the Company, except that
nothing contained herein shall preclude you from purchasing or owning securities
of any such business if such securities are publicly traded, and provided that
your holdings do not exceed one (1%) percent of the issued and outstanding
securities of any class of securities of such business; or

               (ii) either individually or on behalf of or through any third
party, solicit, divert or appropriate or attempt to solicit, divert or
appropriate, for the purpose of competing with the Company or any present or
future parent, subsidiary or other affiliate of the Company which is engaged in
a similar business as the Company, any customers, business partners or patrons
of the Company, or any prospective customers or patrons,

               (iii) either individually or on behalf of or through any third
party, directly or indirectly, solicit, entice or persuade or attempt to
solicit, entice or persuade or hire any other employees of or consultants to the
Company or any present or future parent, subsidiary or affiliate of the Company
to leave the services of the Company or any such parent, subsidiary or affiliate
for any reason.

          (c) Reasonableness of Restrictions. You further recognize and
acknowledge that (i) the types of employment which are prohibited by this
Section 1 are narrow and reasonable in relation to the skills which represent
your principal salable asset both to the Company and to your other prospective
employers, and (ii) the specific but broad geographical scope of the provisions
of this Section 1 is reasonable, legitimate and fair to you in light of the
Company's need to market its services and develop, market and sell its products
in a large geographic area in order to have a sufficient customer base to make
the Company's business profitable and in light of the limited restrictions on
the type of employment prohibited herein compared to the types of employment for
which you are qualified to earn your livelihood.

          (d) Survival of Acknowledgements and Agreements. Your acknowledgements
and agreements set forth in this Section 1 shall survive the expiration or
termination of this Agreement and the termination of your employment with the
Company for any reason.

     2. Protected Information. You shall at all times, both during and after any
termination of this Agreement by either you or the Company, maintain in
confidence and shall not, without the prior written consent of the Company, use,
except in the course of performance of your duties for the Company, disclose or
give to others any fact or information which was disclosed to or developed by
you during the course of performing services for, or receiving training from,
the Company, and is not generally available to the public, including but not
limited to information and facts concerning business plans, customers, future
customers, suppliers,


                                        2

<PAGE>

licensors, licensees, partners, investors, affiliates or others, training
methods and materials, financial information, sales prospects, client lists,
inventions (as defined in Section 3), or any other scientific, technical, trade
or business secret or confidential or proprietary information of the Company or
of any third party provided to the Company during the Term. In the event you are
questioned by anyone not employed by the Company or by an employee of or a
consultant to the Company not authorized to receive such information, in regard
to any such information or any other secret or confidential work of the Company,
or concerning any fact or circumstance relating thereto, you will promptly
notify the president of the Company.

     3. Ownership of Ideas. Copyrights and Patents.

          (a) Property of the Company. You agree that all ideas, discoveries,
creations, manuscripts and properties, innovations, improvements, know-how,
inventions, designs, developments, apparatus, techniques, methods, biological
processes, cell lines, laboratory notebooks and formulae (all of the foregoing
being hereinafter referred to as "the inventions") which may be used in the
business of the Company, whether patentable, copyrightable or not, which you may
conceive, reduce to practice or develop during the Term, alone or in conjunction
with another, or others, whether during or out of regular business hours, and
whether at the request or upon the suggestion of the Company, or otherwise,
shall be the sole and exclusive property of the Company, and that you shall not
publish any of the inventions without the prior written consent of the Company.
You hereby assign to the Company all of your right, title and interest in and to
all of the foregoing. You further represent and agree that to the best of your
knowledge and belief none of the inventions will violate or infringe upon any
right, patent, copyright, trademark or right of privacy, or constitute libel or
slander against or violate any other rights of any person, firm or corporation,
and that you will use your best efforts to prevent any such violation.

          (b) Cooperation. At any time during or after the Term, you agree that
you will fully cooperate with the Company, its attorneys and agents in the
preparation and filing of all papers and other documents as may be required to
perfect the Company's rights in and to any of such inventions, including, but
not limited to, joining in any proceeding to obtain letters patent, copyrights,
trademarks or other legal rights of the United States and of any and all other
countries on such inventions, to defend any judicial, opposition or other
proceedings in respect of such applications and any judicial, opposition or
other proceeding, petition or application for revocation of any such patent,
copyright, trademark or other analogous protection, provided that the Company
will bear the expense of such proceedings, and that any patent or other legal
right so issued to you, personally, shall be assigned by you to the Company
without charge by you.

          (c) Power of Attorney. If the Company is unable, after reasonable
effort, to secure your signature on any application for patent, copyright,
trademark or other analogous registration or other documents regarding any legal
protection relating to the inventions, whether because of your physical or
mental incapacity or for any other reason whatsoever, you hereby irrevocably
designate and appoint the Company and its duly authorized officers and agents as
your agent and attorney-in-fact, to act for and in your behalf and stead to
execute and file any such application or applications or other documents and to
do all other lawfully permitted acts to further the prosecution and issuance of
patent, copyright or trademark registrations or any other legal protection
thereon with the same legal force and effect as if executed by you.


                                        3

<PAGE>

     4. Disclosure to Future Employers. You agree that you will provide, and
that the Company may similarly provide in its discretion, a copy of the
covenants contained in Sections 1, 2 and 3 of this Agreement to any business or
enterprise which you may directly, or indirectly, own, manage, operate, finance,
join, control or in which you participate in the ownership, management,
operation, financing, or control, or with which you may be connected as an
officer, director, employee, partner, principal, agent, representative,
consultant or otherwise.

     5. Records. Upon termination of your relationship with the Company, you
shall deliver to the Company any property of the Company which may be in your
possession including products, materials, memoranda, notes, records, reports, or
other documents or photocopies of the same.

     6. No Conflicting Agreements. You hereby represent and warrant that you
have no commitments or obligations inconsistent with this Agreement and you
hereby agree to indemnify and hold the Company harmless against loss, damage,
liability or expense arising from any claim based upon circumstances alleged to
be inconsistent with such representation and warranty.

     7. General.

          (a) Notices. For purposes of this Exhibit A as well as its
accompanying Employment Agreement, all notices, requests, consents and other
communications hereunder shall be in writing, shall be addressed to the
receiving party's address set forth below or to such other address as a party
may designate by notice hereunder, and shall be either (i) delivered by hand,
(ii) made by telex, telecopy or facsimile transmission, (iii) sent by overnight
courier, or (iv) sent by registered mail, return receipt requested, postage
prepaid.

          If to the Company, at:

               Archemix Corp.
               One Hampshire Street
               Cambridge, MA 02139
               Attn: Board of Directors

          If to the Employee, at:

               Dr. Errol De Souza
               c/o Archemix Corp.
               One Hampshire Street
               Cambridge, MA 02139

          With a copy to:

               Deborah Lifshey
               Consultant
               Pearl Meyer & Partners
               445 Park Ave.


                                        4

<PAGE>

               New York, NY 10022-2606

          All notices, requests, consents and other communications hereunder
shall be deemed to have been given either (i) if by hand, at the time of the
delivery thereof to the receiving party at the address of such party set forth
above, (ii) if made by telex, telecopy or facsimile transmission, at the time
that receipt thereof has been acknowledged by electronic confirmation or
otherwise, (iii) if sent by overnight courier, on the next business day
following the day such notice is delivered to the courier service, or (iv) if
sent by registered mail, on the fifth business day following the day such
mailing is made.

          (b) Entire Agreement. This Agreement embodies the entire agreement and
understanding between the parties hereto with respect to the subject matter
hereof and supersedes all prior oral or written agreements and understandings
relating to the subject matter hereof. No statement, representation, warranty,
covenant or agreement of any kind not expressly set forth in this Agreement
shall affect, or be used to interpret, change or restrict, the express terms and
provisions of this Agreement.

          (c) Modifications and Amendments. The terms and provisions of this
Agreement may be modified or amended only by written agreement executed by the
parties hereto.

          (d) Waivers and Consents. The terms and provisions of this Agreement
may be waived, or consent for the departure therefrom granted, only by written
document executed by the party entitled to the benefits of such terms or
provisions. No such waiver or consent shall be deemed to be or shall constitute
a waiver or consent with respect to any other terms or provisions of this
Agreement, whether or not similar. Each such waiver or consent shall be
effective only in the specific instance and for the purpose for which it was
given, and shall not constitute a continuing waiver or consent.

          (e) Assignment. The Company may assign its rights and obligations
hereunder to any person or entity who succeeds to all or substantially all of
the Company's business or that aspect of the Company's business in which you are
principally involved. Your rights and obligations under this Agreement may not
be assigned by you without the prior written consent of the Company.

          (f) Benefit. All statements, representations, warranties, covenants
and agreements in this Agreement shall be binding on the parties hereto and
shall inure to the benefit of the respective successors and permitted assigns of
each party hereto. Nothing in this Agreement shall be construed to create any
rights or obligations except among the parties hereto, and no person or entity
shall be regarded as a third-party beneficiary of this Agreement.

          (g) Governing Law. This Agreement and the rights and obligations of
the parties hereunder shall be construed in accordance with and governed by the
law of the Commonwealth of Massachusetts, without giving effect to the conflict
of law principles thereof.

          (h)  Jurisdiction and Service of Process. Any legal action or
               proceeding with respect to this Agreement shall be brought in the
               courts of The Commonwealth of Massachusetts or of the United
               States of America for


                                        5

<PAGE>

               the District of Massachusetts. By execution and delivery of this
               Agreement, each of the parties hereto accepts for itself and in
               respect of its property, generally and unconditionally, the
               jurisdiction of the aforesaid courts. Each of the parties hereto
               irrevocably consents to the service of process of any of the
               aforementioned courts in any such action or proceeding by the
               mailing of copies thereof by certified mail, postage prepaid, to
               the party at its address set forth in Section 7(a) hereof.

          (i) Severability. The parties intend this Agreement to be enforced as
written. However, (i) if any portion or provision of this Agreement shall to any
extent be declared illegal or unenforceable by a duly authorized court having
jurisdiction, then the remainder of this Agreement, or the application of such
portion or provision in circumstances other than those as to which it is so
declared illegal or unenforceable, shall not be affected thereby, and each
portion and provision of this Agreement shall be valid and enforceable to the
fullest extent permitted by law; and (ii) if any provision, or part thereof, is
held to be unenforceable because of the duration of such provision or the
geographic area covered thereby, the Company and you agree that the court making
such determination shall have the power to reduce the duration and/or geographic
area of such provision, and/or to delete specific words and phrases
("blue-pencilling"), and in its reduced or blue-pencilled form such provision
shall then be enforceable and shall be enforced.

          (j) Headings and Captions. The headings and captions of the various
subdivisions of this Agreement are for convenience of reference only and shall
in no way modify, or affect the meaning or construction of any of the terms or
provisions hereof.

          (k) Injunctive Relief. You hereby expressly acknowledge that any
breach or threatened breach of any of the terms and/or conditions set forth in
Section 1, 2 or 3 of this Agreement will result in substantial, continuing and
irreparable injury to the Company. Therefore, you hereby agree that, in addition
to any other remedy that may be available to the Company, the Company shall be
entitled to injunctive or other equitable relief by a court of appropriate
jurisdiction in the event of any breach or threatened breach of the terms of
Section 1, 2 or 3 of this Agreement.

          (l) No Waiver of Rights, Powers and Remedies. No failure or delay by a
party hereto in exercising any right, power or remedy under this Agreement, and
no course of dealing between the parties hereto, shall operate as a waiver of
any such right, power or remedy of the party. No single or partial exercise of
any right, power or remedy under this Agreement by a party hereto, nor any
abandonment or discontinuance of steps to enforce any such right, power or
remedy, shall preclude such party from any other or further exercise thereof or
the exercise of any other right, power or remedy hereunder. The election of any
remedy by a party hereto shall not constitute a waiver of the right of such
party to pursue other available remedies. No notice to or demand on a party not
expressly required under this Agreement shall entitle the party receiving such
notice or demand to any other or further notice or demand in similar or other
circumstances or constitute a waiver of the rights of the party giving such
notice or demand to any other or further action in any circumstances without
such notice or demand.

          (m) Expenses. Should any party breach this Agreement, in addition to
all other remedies available at law or in equity, such party shall pay all of
any other party's costs


                                        6

<PAGE>

and expenses resulting therefrom and/or incurred in enforcing this Agreement,
including legal fees and expenses.

          (n) Counterparts. This Agreement may be executed in one or more
counterparts, and by different parties hereto on separate counterparts, each of
which shall be deemed an original, but all of which together shall constitute
one and the same instrument.

     If the foregoing accurately sets forth our agreement, please so indicate by
signing and returning to us the enclosed copy of this letter.

                                        Very truly yours,

                                        Archemix Corp.


                                        By: /s/ Martin Stanton
                                            ------------------------------------
                                            Martin Stanton, President
                                        Date:
                                              ----------------------------------


Accepted and Approved:


/s/ Errol De Souza
-------------------------------------
Dr. Errol De Souza

Date: March 7, 2003


                                        7
<PAGE>

                                                                       Exhibit B

                             FORM: RELEASE OF CLAIMS

     You agree and acknowledge that by signing this Release of Claims and
accepting the consideration reflected in the [Reference to other Employment
Agreement] between you and [Name of Company] (the "Company") and other good and
valuable consideration, you are waiving your right to assert any form of legal
claim against the Company (including any divisions, affiliates, subsidiaries and
related entities, as well as its and their respective officers, directors,
employees, agents, representatives, successors and assigns) of any kind
whatsoever from the beginning of time through the date of this Release of
Claims. Your waiver and release is intended to bar any form of legal claim,
charge, complaint or any other form of action (jointly referred to as "Claims")
against the Company seeking any form of relief including, without limitation,
equitable relief (whether declaratory, injunctive or otherwise), the recovery of
any damages or any other form of monetary recovery whatsoever (including,
without limitation, back pay, front pay, compensatory damages, emotional
distress damages, punitive damages, attorneys fees and any other costs) against
the Company, through the date of this Release of Claims.

     Without limiting the foregoing general waiver and release of claims, you
specifically waive and release the Company from any Claim arising from or
related to your employment relationship with the Company or the termination
thereof, including, without limitation:

     (a) Claims under any local, state or federal discrimination, fair
employment practices or other employment related statute, regulation or
executive order (as they may have been amended through the date of this Release
of Claims) prohibiting discrimination or harassment based upon any protected
status including, without limitation, race, national origin, age, gender,
marital status, disability, veteran status or sexual orientation. Without
limitation, specifically included in this paragraph are any Claims arising under
the federal Age Discrimination in Employment Act, the Older Workers Benefit
Protection Act, the Civil Rights Acts of 1866 and 1871, Title VII of the Civil
Rights Act of 1964, the Civil Rights Act of 1991, the Equal Pay Act, the
Americans With Disabilities Act, and any similar statute;

     (b) Claims under any other local, state or federal employment related
statute, regulation or executive order (as they may have been amended through
the date of this Release of Claims) relating to wages, hours or any other terms
and conditions of employment. Without limitation, specifically included in this
paragraph are any Claims arising under the Fair Labor Standards Act, the Family
and Medical Leave Act of 1993, the National Labor Relations Act, the Employee
Retirement Income Security Act of 1974, the Consolidated Omnibus Budget
Reconciliation Act of 1985 ("COBRA") and any similar statute;

     (c) Claims under any local, state or federal common law theory including,
without limitation, wrongful discharge, breach of express or implied contract,
promissory estoppel, unjust enrichment, breach of a covenant of good faith and
fair dealing, violation of public policy, defamation, interference with
contractual relations, intentional or negligent infliction of emotional
distress, invasion of privacy, misrepresentation, deceit, fraud or negligence;
<PAGE>

     (d) Claims under any local, state or federal securities law, including,
without limitation, the Securities Act of 1933, as amended, the Securities
Exchange Act of 1934, as amended, and any Delaware, Massachusetts or other state
or local securities statutes and regulations; and

     (e) Any other Claim arising under local, state or federal law.

     You acknowledge and agree that, but for providing this waiver and release
of claims, you would not be receiving the consideration reflected in the
[Reference to Other Employment Agreement].

     YOU EXPLICITLY ACKNOWLEDGE THAT BECAUSE YOU ARE OVER FORTY (40) YEARS OF
AGE, YOU HAVE SPECIFIC RIGHTS UNDER THE OWBPA, WHICH PROHIBITS DISCRIMINATION ON
THE BASIS OF AGE, AND THAT THE RELEASES SET FORTH IN THIS SECTION ARE INTENDED
TO RELEASE ANY RIGHT THAT YOU MAY HAVE TO FILE A CLAIM AGAINST THE COMPANY
ALLEGING DISCRIMINATION ON THE BASIS OF AGE.

     IT IS THE COMPANY'S DESIRE AND INTENT TO MAKE CERTAIN THAT YOU FULLY
UNDERSTAND THE PROVISIONS AND EFFECTS OF THIS RELEASE OF CLAIMS. TO THAT END,
YOU HAVE BEEN ENCOURAGED AND GIVEN THE OPPORTUNITY TO CONSULT WITH LEGAL COUNSEL
FOR THE PURPOSE OF REVIEWING THE TERMS OF THIS AGREEMENT. CONSISTENT WITH THE
PROVISIONS OF OWBPA, THE COMPANY HAS PROVIDED YOU WITH AT LEAST TWENTY-ONE (21)
DAYS IN WHICH TO CONSIDER AND ACCEPT THE TERMS OF THIS RELEASE OF CLAIMS. IN
ADDITION, YOU MAY RESCIND YOUR ASSENT TO THIS RELEASE OF CLAIMS WITHIN SEVEN (7)
DAYS AFTER YOU SIGN AND SUBMIT IT. TO DO SO, YOU MUST DELIVER A WRITTEN NOTICE
OF RESCISSION TO [THE BOARD AND OTHER DESIGNATED COMPANY OFFICIAL] AT [ADDRESS].
TO BE EFFECTIVE, SUCH RESCISSION MUST BE HAND DELIVERED OR POSTMARKED WITHIN THE
SEVEN (7) DAY PERIOD AND SENT BY CERTIFIED MAIL, RETURN RECEIPT REQUESTED, TO
[COMPANY OFFICIALS AND ADDRESS].

     Consistent with the provisions of the OWBPA and other federal
discrimination laws, nothing in this release shall be deemed to prohibit you
from challenging the validity of this release under the federal age or other
discrimination laws (the "Federal Discrimination Laws") or from filing a charge
or complaint of age or other employment- related discrimination with the Equal
Employment Opportunity Commission ("EEOC"), or from participating in any
investigation or proceeding conducted by the EEOC. Further, nothing in this
Release of Claims shall be deemed to limit the Company's right to seek immediate
dismissal of such charge or complaint on the basis that your signing of this
Agreement constitutes a full release of any individual rights under the Federal
Discrimination Laws, or to seek restitution to the extent permitted by law of
the economic benefits provided to you under this Agreement in the event that you
successfully challenge the validity of this release and prevail in any claim
under the Federal Discrimination Laws.

     This Agreement shall be deemed to have been made in Massachusetts, and the
validity, interpretation and performance of this Agreement shall be governed by
the internal law of Massachusetts, without giving effect to conflict of law
principles. Both parties agree that any
<PAGE>

action, demand, claim or counterclaim relating to the terms and provisions of
this Agreement, or to its breach, shall be commenced in a court of competent
jurisdiction in Massachusetts and that venue shall lie exclusively in Middlesex
or Suffolk County Massachusetts. Both parties further agree that any action,
demand, claim or counterclaim shall be resolved by a judge alone, and both
parties hereby waive and forever renounce the right to a trial before a civil
jury. The provisions of this Agreement are severable, and if for any reason any
part hereof shall be found to be unenforceable, the remaining provisions shall
be enforced in full. By signing this Release of Claims, you give the Company
assurance that you have read and understood all of its terms; that you have had
a full and reasonable opportunity to consider its terms and that you have signed
this Release of Claims knowingly and voluntarily.

[Name of Executive]                     [Name of Company]


                                        By:
-------------------------------------       ------------------------------------
Dated:                                  Dated:
       ------------------------------          ---------------------------------