GRAPHIC

Exhibit 10.1

August 6,
2010

[NAME
OF EMPLOYEE]
[ADDRESS]

Dear
[FIRST NAME]:

This
letter agreement (this "Agreement") sets forth the arrangements between Helicos BioSciences Corporation (the
"Company") and you in connection with your continued employment with the Company as it considers alternatives to its existing long-term
strategic focus, including a repositioning of the Company in the genetic analysis markets. We would like to retain your focused and committed efforts during this period of uncertainty in exchange for
the benefits and incentives detailed in this Agreement in addition to other compensation you may earn from your service to the Company.

1.Restricted Stock Award

(a)Award.Upon the fifth (5th) business day after the Company's shareholders approve an increase
in the number of shares reserved for issuance under the Company's 2007 Stock and Option Incentive Plan or a successor plan (the "2007 Plan"), the
Company agrees to grant you a restricted stock award ("Award") of the Company's common stock, par value $0.001 per share
("Common Stock"), under the 2007 Plan in the amount of [NUMBER] shares. The Award will vest according to the following vesting
schedule (the "Vesting Schedule"):

January 1, 2011


12.5%July 1, 2011


12.5%January 1, 2012


12.5%July 1, 2012


12.5%January 1, 2013


12.5%July 1, 2013


12.5%January 1, 2014


12.5%July 1, 2014


12.5%100%


Your
Award will be documented by and shall be subject to the terms of the 2007 Plan and the Company's standard Restricted Stock Award Agreement that will be entered into between you and
the Company.

(b)Contingency for Available Shares.If, upon any increase in the number of shares reserved under the 2007 Plan
(including by way of Company shareholder approval or the evergreen provisions contained in the 2007 Plan), there are insufficient shares available under the 2007 Plan to satisfy your Award and all
similar restricted stock awards to other members of the Company's management team pursuant to letter agreements similar to this Agreement, you and such other members of the Company's management team
will receive a pro rata portion of available shares in respect of such restricted stock awards until sufficient shares are reserved thereafter under the 2007 Plan, if ever. Please note that the
Company cannot guarantee that shareholder approval of an increase in the number of shares reserved under the 2007 Plan will be received.

---



(c)Change in Control Protection.If, prior to the issuance of your entire Award or Anti-Dilution
Award(s) (as defined below), there is a Terminating Event (as defined below) within twelve (12) months after the consummation of a Change in Control of the Company (as defined below), the
Company or its successor in such Change in Control (as the case may be) shall make (x) a lump sum cash payment to you in respect of such unissued portion of your Award and
Anti-Dilution Award(s), as applicable, in an amount equal to the fair market value of such unissued portion of your Award and Anti-Dilution Award(s), as applicable, determined
immediately prior to the consummation of such Change in Control or (y) appropriate provision for the substitution of the unissued portion of your Award and Anti-Dilution Award(s),
as applicable, with new awards of securities of the Company, its successor in such Change in Control, or the parent entity of the Company or such successor, with appropriate adjustment as to the
number and kind of securities as the Committee (as defined below) shall specify. For clarity, any portion of your Award and Anti-Dilution Award(s) actually issued in advance of any Change
in Control shall be governed by the terms of the Restricted Stock Award Agreement between you and the Company in respect thereof, the 2007 Plan, the Change in Control Agreement between you and the
Company and any other applicable agreement between you and the Company and not by the preceding sentence.



(d)Anti-Dilution Protection.



2

---





2.Cash/Unrestricted Stock Award.

(a)Award and Timing of Payment.The Company shall grant you a retention award having a value of
$[AMOUNT] (the "Cash/Stock Payment") upon the following schedule and terms.



(b)Form of Award.The compensation committee (the "Committee") of the Company's board of directors will
determine whether to make your Cash/Stock Payment in a lump sum cash payment or in the form of shares of unrestricted Common Stock within thirty-five (35) trading days after the
closing of the financing referred to in Section 2(a)(i). If the Committee determines to pay the Cash/Stock Payment in shares of unrestricted Common Stock:



3

---





3.Impact of this Agreement on Employment and Other Agreements.

Notwithstanding
anything to contrary herein, your employment shall be deemed an employment at will and your employment may be terminated at will by you or the Company at anytime for any
or no reason except that you agree to give the Company written notice at least thirty (30) calendar days in advance of you terminating your employment, provided that the Company may waive any
obligation to continue your employment after such written notice is received. The benefits to which you are entitled hereunder are in addition to the benefits to which you may be entitled under any
other agreements with the Company except that (i) payments hereunder may be limited by, and deemed to be "Severance Payments" under, Section 5 of your Change in Control Agreement with
the Company and (ii) the Award and Anti-Dilution Award(s), if and to the extent actually issued, shall be governed by the terms of the Restricted Stock Award Agreement between you
and the Company in respect thereof, the 2007 Plan, the Change in Control Agreement between you and the Company and any other applicable agreement between you and the Company in respect of equity
awards generally. Except as provided in Section 1(c), the benefits to which you are entitled hereunder will terminate in connection with the termination of your employment.

4.Section 409A.

Notwithstanding
anything in this Agreement to the contrary, in the event that any benefits payable or otherwise provided under this Agreement would be deemed to constitute
non-qualified deferred compensation subject to Section 409A of the Internal Revenue Code of 1986, as amended ("Section 409A"),
you and the Company shall adjust the terms of such payment or benefit in a commercially reasonable manner to comply in good faith with the requirements of Section 409A and to avoid the
imposition of any excise tax or other penalty with respect to such payment or benefit under Section 409A, including agreeing to delay the receipt of any payments to a six-month wait
after your separation from service.

5.Miscellaneous.

(a)Entire Agreement.This Agreement sets forth the entire agreement between the parties hereto with respect to
its subject matter, and supersedes and replaces any and all previous oral or written communications, representation, promises or agreements between the parties relating to this subject.

(b)Amendment.This Agreement may not be changed or otherwise modified except by an instrument in writing signed
by you and an authorized representative of the Company.

(c)Governing Law.This Agreement shall be governed by and construed in accordance with the laws of
Massachusetts.

(d)No Waiver.The failure of the Company or you to insist upon strict adherence to any term of this Agreement
on any occasion shall not be considered a waiver of such party's rights or deprive such party of the right thereafter to insist upon strict adherence to that term or any other term of this Agreement.

(e)Severability.In the event that anyone or more of the provisions of this Agreement shall be or become
invalid, illegal or unenforceable in any respect, the validity, legality and enforceability of the remaining provisions of this Agreement outstanding shall not be affected thereby.

4

---



(f)Arbitration.Any claim or controversy arising from your employment with the Company, the termination of your
employment, this Agreement, or any other related matter will be resolved by final and binding arbitration under the Employment Dispute Resolution Rules of the American Arbitration Association. This
arbitration remedy will be exclusive. To invoke the arbitration remedy, the complaining party must give notice in writing to the other party and to the American Arbitration Association of his or its
intention to arbitrate within the statue of limitations applicable to the controversy and must first submit the matter to a non-binding mediation before a mediator agreed upon by the
parties. The arbitrator will have the authority to grant the same remedies that could be awarded by a court of competent jurisdiction. The arbitrator will issue findings of fact and conclusions of law
supporting the award. The losing party in any such dispute will pay all of the winning party's costs, including any arbitrator or administrative fees and reasonable attorneys' fees. Any arbitration
will be held in Massachusetts.

(g)Notice.For the purpose of this Agreement, notices and all other communications provided for in this
Agreement shall be in writing and shall be deemed to have been duly given when delivered or mailed by United States registered mail, return receipt requested, postage prepaid, addressed to the
respective addresses set forth on the execution page of the letter agreement,providedthat all notices to the Company shall be directed to the
attention of the General Counsel of the Company, or to such other address as either party may have furnished to the other in writing in accordance herewith, except that notice of change of address
shall be effective only upon receipt.

(h)Withholding Taxes.The Company may withhold from any amounts payable under this Agreement such U.S. federal,
state and local taxes as may be required to be withheld pursuant to any applicable law or regulation.

(i)Counterparts.This Agreement may be signed in counterparts, each of which shall be an original, with the
same effect as if the signatures thereto and hereto were upon the same instrument.

Sincerely,By:

Company Representative


Accepted and Agreed:By:

[NAME OF EMPLOYEE]


5

---



QuickLinks