SEPARATION AGREEMENT AND RELEASE

This Separation Agreement and Release (the “Agreement”) is dated July 12 2007,
and is effective on the date described in Section 14. This Agreement is made as
a mutually agreed compromise between the Parties (as defined below) for the
complete and final settlement of all claims, differences, and alleged causes of
action existing between them as of the Effective Date.

PARTIES

The Parties to this Agreement are Encysive Pharmaceuticals Inc. (the “Company”)
and Bruce D. Given, M.D. (the “Executive”). The Company and the Executive are
referred to collectively as the “Parties.”

PREAMBLE

WHEREAS, the Executive was previously employed as the President and Chief
Executive Officer of the Company, pursuant to that certain Termination Agreement
dated March 21, 2003, as amended from time to time (the “Termination
Agreement”);

WHEREAS, the Parties intend to terminate the Termination Agreement as of the
Effective Date (except with respect to the Executive’s and the Company’s
continuing obligations under Sections 6.3(a)(2), 6.3(b) – (e), 8, 9, 10, 12 and
13.8 and Exhibits C and D thereof) and enter into this Agreement;

WHEREAS, the Parties intend that this Agreement shall operate as a complete and
final settlement of all claims, differences and alleged causes of action
existing between them as of the Effective Date of this Agreement;

WHEREAS, the Executive has had at least 21 days to consider this Agreement;

WHEREAS, the Company has advised the Executive in writing to consult with
independent counsel respecting this Agreement;

WHEREAS, the Executive has had an opportunity to consult with independent
counsel with respect to the terms, meaning and effect of this Agreement; and

WHEREAS, the Executive understands that the Company regards the above
representations as material and that the Company is relying on these
representations in entering into this Agreement.

NOW, THEREFORE, in consideration of the mutual promises and obligations
contained and exchanged in this Agreement and other good and valuable
consideration, the receipt and sufficiency of which is hereby acknowledged, the
Parties agree as follows:

1. Definitions.

1.1 “Company and/or its Affiliates” means and includes the Company, its
Affiliates, and all of their predecessors, successors and assigns and parents,
subsidiaries, divisions or other affiliated companies, partners, partnerships,
present and former officers, directors, employees, stockholders, agents,
employee benefit plans or programs and their fiduciaries, whether in their
individual or official capacities and all of the successors and assigns of the
foregoing. “Affiliates” also includes a person or entity who, directly or
indirectly through one or more intermediaries, controls, is controlled by, or is
under common control with, the Company.

1.2 “Date of Termination” means June 24, 2007.

Capitalized terms used but not otherwise defined herein shall have the meanings
ascribed to such terms in the Termination Agreement as defined therein unless
otherwise defined herein.

2. Termination of the Termination Agreement. The Parties agree that the
Termination Agreement is hereby terminated and of no further force and effect as
of the Effective Date, except with respect to the Executive’s and the Company’s
obligations under Section 6.3(a)(2) and (b) – (e), Good Reason; Without Cause;
Nonrenewal; Section 8, Executive’s Confidentiality Obligation; Section 9,
Disclosure of Information Ideas, Concepts, Improvements, Discoveries and
Inventories; Section 10, Ownership of Information, Ideas, Concepts,
Improvements, Discoveries, and Inventions and all Original Works of Authorship;
Section 12, Executive’s Non-Competition Obligation; and Section 13.8, Defense of
Claims, all of which survive the termination of the Termination Agreement. This
Agreement shall have no effect on Executive’s Indemnification Agreement
(attached as Exhibit C to the Termination Agreement), the Company’s D&O
insurance policy (summarized in Exhibit D of the Termination Agreement) and any
agreement or plan governing Executive’s equity incentive awards (e.g., stock
options and/or restricted stock).

3. Pay Through Date of Termination. The Executive acknowledges that he has
received all salary, wages and other compensation earned on or before the Date
of Termination. The Company agrees it shall pay Executive for all unused
vacation time he accrued through the Date of Termination, as specified in
Exhibit A, subject to such payroll and withholding deductions as may be required
by law.

4. Resignation by the Executive. Effective as of the date the Executive signs
this Agreement, the Executive hereby resigns from all positions he holds with
the Company and/or its Affiliates, including as a member of the Company’s Board
of Directors. The Executive’s employment with the Company was terminated
effective June 24, 2007.

5. Payments to the Executive. The Parties hereby agree that, subject to the
Executive’s execution of this Agreement containing a release from liability and
waiver of right to sue the Company and/or its Affiliates, the Company agrees to
make the payments and continue the benefits provided for in Sections 6.3(a)(2)
and 6.3(b) – (e) of the Termination Agreement, as further modified and specified
in Exhibit A attached hereto, subject to such payroll and withholding deductions
as may be required by law. Notwithstanding any of the above to the contrary, if
there is a Change of Control (as that term is defined under the Company’s
Amended and Restated 1999 Stock Incentive Plan and 2007 Incentive Plan, as
amended (each, a “Plan”)) during the twelve month period following the Date of
Termination, the Executive’s outstanding and unvested stock options and/or
restricted stock shall accelerate in accordance with the terms of the applicable
Plan. Further, the Executive will not be entitled to any of the benefits or
payments provided in Sections 6.3(a)(2) and 6.3(c) — (e) of the Termination
Agreement if the Executive breaches this Agreement or the provisions of
Sections 8, 9, 10, or 12 of the Termination Agreement.

6. Release by the Executive. The Executive unconditionally, fully and forever
waives, releases, discharges, agrees to hold harmless, and promises not to sue
the Company and/or its Affiliates, from and for any claim, action or right of
any sort, known or unknown, arising on or before the Effective Date.

6.1 This release includes, but is not limited to, any claim arising out of or
related to the following: any claim for any wages, salary, compensation, sick
time, vacation time, paid leave or other remuneration of any kind; any claim for
additional or different compensation or benefits of any sort, including any
participation in any severance pay plan; any claim of discrimination or
retaliation on the basis of age, race, sex, religion, marital status, sexual
preference, national origin, handicap or disability, veteran status, or special
disabled veteran status; any claim arising under Title VII of the Civil Rights
Act of 1964, the Civil Rights Act of 1991, the Age Discrimination in Employment
Act of 1967, the Employee Retirement Income Security Act of 1974, the Americans
with Disabilities Act, the Family and Medical Leave Act, the Fair Labor
Standards Act of 1938, the Texas Commission on Human Rights Act, Chapter 451 of
the Texas Labor Code, or the Texas Payday Law, as such statutes may be amended
from time to time; any other claim based on any statutory prohibition; any claim
arising out of or related to an express or implied employment contract, any
other contract affecting terms and conditions of employment, or a covenant of
good faith and fair dealing; any tort claim or other claim for personal injury,
death or property damage or loss; any claim for fraud or misrepresentation; and
any personal gain with respect to any claim arising under any whistleblower or
qui tam provisions of any state or federal law.

6.2 The Executive represents that the Executive has read and understands this
release provision and that rights and claims under the Age Discrimination in
Employment Act of 1967 are among the rights and claims against the Company that
the Executive is releasing. The parties further acknowledge and agree that the
Executive is not releasing any of the following: (i) any rights or claims
arising after the Date of Termination, (ii) any rights or claims arising from or
related to any obligations that are stated or affirmed in this Agreement,
(iii) any rights or claims for indemnification pursuant to any applicable
contract, policy, bylaw, or law (including but not limited to the Executive’s
Indemnification Agreement with the Company dated March 21, 2002 or the Company’s
D&O insurance policy), (iv) any rights or claims under any agreement or plan
governing the Executive’s equity incentive awards (e.g., stock options or
restricted stock), and (v) any rights or claims that may not be released as a
matter of law (for example, claims for unemployment insurance).

7. Consideration. As consideration for the Executive’s execution and performance
of his obligations under this Agreement, the Company will perform its remaining
obligations pursuant to this Agreement.

8. Future Employment. The Executive agrees not to seek or accept employment with
the Company and/or its current Affiliates and acknowledges that the Company
and/or its current Affiliates are not obligated to offer employment to the
Executive, now or in the future. Notwithstanding the foregoing, nothing in this
Agreement shall preclude or prevent the Executive from seeking employment with
or becoming employed by an individual or entity that becomes an Affiliate of the
Company following the Date of Termination.

9. No Other Claims. The Executive represents that the Executive has not filed or
authorized the filing of any complaints, charges or lawsuits against the Company
and/or its Affiliates with any federal, state or local court, governmental
agency, or administrative agency, and that if, unbeknownst to the Executive, any
such complaint has been filed on the Executive’s behalf, the Executive will use
the Executive’s best efforts to cause it to be withdrawn immediately and
dismissed with prejudice.

10. Confidentiality and Defense of Claims. Both Parties shall keep strictly
confidential all the terms and conditions, including amounts payable, in the
Agreement and shall not disclose them to any person other than legal and/or
financial advisors, government officials who seek such information in the course
of their official duties, individuals at the Company responsible for
implementing the Agreement, and the Executive’s spouse, unless compelled to do
so by law or regulation, or business necessity (including the requirement to
file this Agreement with the Securities and Exchange Commission or tax reporting
obligations). Nothing in this Section is intended to prevent the Executive from
disclosing the fact that he was employed by the Company or from describing his
employment duties.

11. Consultation With Counsel. The Company advises the Executive to consult with
independent counsel prior to executing this Agreement, and the Executive
acknowledges being given that advice.

12. No Defamatory Statements. The Executive agrees that he will refrain from
making any representation, statement, comment or any other form of communication
(hereinafter collectively referred to as “representation”), whether written or
oral, to any person or entity, including but not limited to the principals,
officers, directors, employees, advisors, agents, customers, suppliers and
competitors of the Company and/or its Affiliates, or any government officials,
which representation has the effect or tendency to disparage, denigrate, or
otherwise reflect negatively on the Company and/or its Affiliates and/or their
business, officers, directors, shareholders, employees, agents, advisors or
investors. The Company agrees it will take all reasonable steps to ensure that
the Company and its officers, directors, and employees refrain from making any
external representation that would have the effect or tendency to disparage,
denigrate, or otherwise reflect negatively on the Executive. For purposes of any
Company-sponsored public statements or responses to inquiries about the
Executive’s employment, the Company shall only provide the following
information: (i) Executive’s dates of employment and positions held, and (ii) a
statement that Executive’s employment with the Company was terminated effective
June 24, 2007.

13. Return of Company Materials. The Executive agrees to deliver to the Company
promptly after the Date of Termination all originals and copies of Company
materials and all other property of the Company and/or its Affiliates in the
Executive’s possession, custody or control.

14. Revocation of Agreement; Effective Date. The Executive, at the Executive’s
sole discretion, may revoke this Agreement on or before the expiration of seven
calendar days after signing it. Revocation shall be in writing and effective
upon dispatch to the following: Paul S. Manierre, General Counsel, Encysive
Pharmaceuticals Inc., 4848 Loop Central Drive, 7th Floor, Houston, Texas 77081.
If the Executive elects to revoke the Agreement, all of the provisions of the
Agreement shall be void and unenforceable. If the Executive does not so elect,
the Agreement shall become effective at the expiration of the revocation period
(i.e., on the eighth day after the Executive signs the Agreement) (the
“Effective Date”).

15. Miscellaneous.

15.1 The Parties acknowledge that this Agreement is the result of a compromise
and shall never be construed as, or said by either of them to be, an admission
by the other of any liability, wrongdoing, or responsibility. The Parties
expressly disclaim any such liability, wrongdoing, fault, or responsibility.

15.2 This Agreement constitutes the entire agreement between the Parties, except
to the extent that it expressly incorporates provisions of the Termination
Agreement. This Agreement shall have no effect on the Executive’s
Indemnification Agreement (attached as Exhibit C to the Termination Agreement),
the Company’s D&O Insurance policy (as summarized in Exhibit D to the
Termination Agreement) and any agreement or plan governing the Executive’s
equity incentive awards (e.g., stock options or restricted stock), and all such
agreements, plans or policies shall remain in effect. This Agreement may be
executed in identical counterparts, each of which shall constitute an original
and both of which shall constitute one and the same agreement. Except as
expressly provided herein, this Agreement supersedes the Termination Agreement
and any severance benefit plan or program and any bonus program at the Company
and/or its Affiliates.

15.3 The Parties understand and agree that any breach of the terms of this
Agreement may give rise to liability for money damages and other legal or
equitable relief.

15.4 The Parties warrant that no representations have been made other than those
contained in the written provisions of this Agreement, and that they do not rely
on any representations not stated in this Agreement.

15.5 The Parties further warrant that they or their undersigned representatives
are legally competent and fully authorized to execute and deliver this
Agreement.

15.6 The Parties confirm they have had the opportunity to have this Agreement
explained to them by independent counsel of their choice, and that they execute
this Agreement freely, knowingly and voluntarily. The Company is relying on its
own judgment and on the advice of its independent counsel and not upon any
recommendation of the Executive or his agents, independent counsel or other
representatives. Likewise, the Executive is relying on his own judgment and on
the advice of his independent counsel, and not upon any recommendation of the
Company or its directors, officers, employees, agents, independent counsel or
other representatives. By voluntarily executing this Agreement, both Parties
confirm their competence to understand and do hereby accept the terms of this
Agreement as resolving fully all differences, disputes and claims that may exist
within the scope of this Agreement.

15.7 This Agreement may not be modified or amended except by a writing signed by
both Parties. No waiver of this Agreement or of any of the promises,
obligations, terms, or conditions contained in it shall be valid unless it is in
writing signed by the Party against whom the waiver is to be enforced. The
waiver by either Party hereto of a breach of any provision of this Agreement
shall neither operate nor be construed as a waiver of any subsequent breach by
any Party. Except as expressly provided for herein, the failure of either Party
hereto to take any action by reason of any breach will not deprive such Party of
the right to take action at any time while such breach occurs.

15.8 If any part or any provision of this Agreement shall be finally determined
to be invalid or unenforceable under applicable law by a court of competent
jurisdiction, that part shall be ineffective to the extent of such invalidity or
unenforceability only, without in any way affecting the remaining parts of said
provision or the remaining provisions of the Agreement.

15.9 The Parties have cooperated in the preparation of this Agreement. Hence,
the Agreement shall not be interpreted or construed against or in favor of
either Party by virtue of the identity, interest, or affiliation of its
preparer.

15.10 This Agreement is made and shall be enforced pursuant to the laws of the
State of Texas, without regard to its law governing conflicts of law.

15.11 The amount of benefits payable under this Agreement shall be paid from the
general assets of the Company and there shall be no separate trust established
to pay any benefits under this Agreement.

15.12 All payments and benefits payable under this Agreement shall be subject to
all applicable federal, state and local taxes and tax requirements and any
elections by the Executive for payouts or deferrals under any Company benefit
plan or program.

15.13 This Agreement shall be binding on and inure to the benefit of the
successors and assigns of the Parties. No rights or obligations, benefits of or
payments to the Executive under this Agreement may be subject to claims of the
Executive’s creditors, or in any manner may be assigned or transferred by the
Executive other than his rights to compensation and benefits that are
transferred by will or to his estate by operation of law.

15.14 All notices and other communications required or permitted hereunder or
necessary or convenient in connection herewith shall be in writing and shall be
deemed to have been given when (i) delivered by hand or sent by facsimile, or
(ii) on the third business day following deposit in the United States mail by
registered or certified mail, return receipt requested, to the addresses as
follows (provided that notice of change of address shall be deemed given only
when received):

If to the Company to:

Encysive Pharmaceuticals Inc.

4848 Loop Central Drive, Suite 700

Houston, Texas 77081

Attention: General Counsel
Facsimile No.: (713) 782-8232

If to the Executive to:

Bruce D. Given, M.D.

2702 Sabine Court

Pearland, Texas 77584

or to such other addresses as the Company or the Executive, as the case may be,
shall designate by notice to the other party hereto in the manner specified in
this Section 15.14.

15.15 Titles and headings to Sections are for the purpose of reference only and
shall in no way limit, define or otherwise affect the provisions hereof. Any and
all Exhibits referred to in this Agreement are, by such reference, incorporated
herein and made a part hereof for all purposes. The words “herein”, “hereof”,
“hereunder” and other compounds of the word “here” shall refer to the entire
Agreement and not to any particular provision hereof.

15.16 Wherever appropriate to the intention of the parties hereto, the
respective rights and obligations of said parties, including, but not limited
to, the rights and obligations set forth in Sections 10 through 13 hereof and
this Section 15, shall survive any termination or expiration of this Agreement.

15.17 Section 13.8 of the Termination Agreement shall be revised to add the
following at the end thereof:

“To the extent that Section 409A of the Internal Revenue Code of 1986, as
amended (the “Code”), is applicable to the expenses under this Section 13.8, and
to the extent that no exception under Code Section 409A is applicable the
following shall apply: (a) all expenses that are taxable and includable in
income to be paid under this Section 13.8 shall only be paid if such expenses
are incurred during the statutory period for which a claim may be made through
the period in which any arbitration or litigation is completed, including all
appeals (provided no period shall exceed 10 years); (b) any amount reimburseable
or paid in one year shall not affect the amount to be reimbursed or paid in
another tax year; (c) the Executive must provide the Company with reasonable
documentation of such expenses; (d) payments for such expenses will be made in
cash within 30 days after the expenses are incurred but in no event later than
the end of Executive’s taxable year in which the expenses are incurred; and
(e) the payments under this Section 13.8 cannot be substituted for another
benefit. However, no payments subject to the foregoing shall be made during the
six-month period commencing the day after the Date of Termination (the “Waiting
Period”), and on January 2, 2008, the Company shall pay Executive a cash lump
sum equal to the amount of the expenses incurred during the Waiting Period that
would have otherwise been payable during such Waiting Period.”

15.18 Notwithstanding anything herein to the contrary, if Executive is a
“specified employee” within the meaning of Code Section 409A on the date of his
separation from service, any payments or benefits hereunder that are deferred
compensation under Code Section 409A will not be paid during the Waiting Period
and on January 2, 2008 all payments and benefits that were payable during the
Waiting Period will be paid to Executive in a cash lump sum payment and
thereafter payments and benefits will be paid as provided herein.

15.19 This Agreement may be executed in more than one counterpart, each of which
shall be deemed to be an original, and all of which together shall constitute
one and the same document.

[SIGNATURE PAGE FOLLOWS]

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IN WITNESS WHEREOF, the undersigned, intending to be legally bound, have
executed this Agreement as of the date indicated below

     
 
  ENCYSIVE PHARMACEUTICALS INC.
(“Company”)
By: /s/ George W. Cole
 
   
BRUCE D. GIVEN, M.D. (“Executive”)
/s/ Bruce D. Given, M.D.
  Name: George W. Cole
—
Title: President & CEO
 
   
Date: 12 July 2007
  Date:July 12, 2007
 
   

          THE STATE OF COLORADO     §           §     COUNTY OF SUMMIT     §

BEFORE ME, the undersigned authority, on this day personally appeared Bruce D.
Given, M.D. who, being by me first duly sworn, upon his oath deposed and stated
that he has read the foregoing Agreement; that he has been advised to discuss
the provisions of this Agreement with an attorney of his choice before signing
it; that he fully understands the terms and conditions of this Agreement; that
he is legally competent to execute this Agreement; and that he has voluntarily
executed this Agreement for the purposes and consideration therein expressed.

Given under my hand and seal of office on this 12th day of July, 2007.

[SEAL]

/s/ Susan C. Price     

NOTARY PUBLIC IN AND FOR

THE STATE OF Colorado

     
THE STATE OF TEXAS
COUNTY OF HARRIS
  §
§
§

BEFORE ME, the undersigned authority, on this day personally appeared George W.
Cole, who being by me first duly sworn, upon his oath deposed and stated that he
is the President and Chief Executive Officer of Encysive Pharmaceuticals Inc.
(the “Company”); that he has read the foregoing Agreement; that he has discussed
the provisions of this Agreement with any attorney of his choice; that he fully
understands the terms and conditions of this Agreement; that he is legally
competent and fully authorized to execute this agreement on behalf of the
Company; and that he has voluntarily executed this Agreement for the purposes
and consideration therein expressed.

Given under my hand and seal of office on this 12th day of July, 2007.

[SEAL]

/s/ Heather P. Woltz     

NOTARY PUBLIC IN AND FOR

THE STATE OF TEXAS

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Exhibit A

  1.   Executive’s unused accrued vacation as of Date of Termination: 40 hours
at $235.57 per hour for a total of $9,422.80.

  2.   Executive’s bonus payment pursuant to Section 6.3(a)(2) of Termination
Agreement: Such amounts, if any, will be paid in accordance with
Section 6.3(a)(2) of the Termination Agreement.

  3.   Executive’s compensation previously deferred and earned and not yet paid
by the Company pursuant to 6.3(a)(3) of Termination Agreement: $0.00.

  4.   Executive’s expense reimbursement pursuant to Section 6.3(b) of
Termination Agreement: Executive will submit his final expense reports on or
before August 31, 2007, and Executive and Company will each use reasonable
efforts to cooperate so that such reports will be sumitted on or before
August 31, 2007. Within 30 days after receipt of such reports, the Company will
pay such expenses, which are reimbursable under Company policy in effect on the
Date of Termination up to a maximum amount of $30,000.

  5.   Benefits to continue pursuant to Section 6.3(c) of Termination Agreement
(subject to terms and conditions stated therein): Medical, dental and vision
coverage for Dr. Given and his wife and son.

  6.   Salary continuation amount pursuant to Section 6.3(d) of Termination
Agreement: The Company is required to pay the Executive $40,833.33 per month for
period of 12 months following Date of Termination. The Company has previously
paid the Executive his salary through June 29, 2007. No other payments of salary
continuation shall be made during the Waiting Period (as defined in
Section 15.17 hereof), and on January 2, 2008, the Company shall pay a cash lump
sum (subject to payroll and withholding deductions) equal to the amount of
salary continuation that would have otherwise been paid during the Waiting
Period. Thereafter, the remaining salary continuation payments will made for the
balance of the 12 month period at the rate of $40,833.33 (before withholding)
per month such that at the end of such period the Company has paid Executive in
the aggregate payments equal to $490,000 (before withholding) of salary
continuation payments under this Agreement.

  7.   Stock option/restricted stock to vest pursuant to Section 6.3(e) of
Termination Agreement: In the event of a Change in Control (as that term is
defined in each of the Plans during the twelve month period following the
Executive’s Date of Termination (as that term is defined in the Separation
Agreement and Release to which this Exhibit is attached), the Executive’s
outstanding unvested stock options/restricted stock will accelerate in
accordance with the terms of the applicable Plan. Exhibit B hereto lists all of
the Executive’s outstanding stock option and restricted stock awards and their
respective vesting schedules.

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