<jats:p> <jats:italic> <jats:italic>Abstract</jats:italic> — </jats:italic> — We previously demonstrated a differential activation of the endothelin-1 (ET-1) pathway in male and female deoxycorticosterone (DOCA)-salt hypertensive rats, with the male rats exhibiting marked alterations in vascular and pressor responses to ET-1 and Suc-[Glu, <jats:sup>9</jats:sup> Ala <jats:sup>11,15</jats:sup> ]-ET-1(8-21) (IRL-1620), an ET <jats:sub>B</jats:sub> agonist. Mechanisms underlying these gender differences are unclear, and we hypothesized that the ovarian hormones attenuate vascular ET <jats:sub>B</jats:sub> responses in female DOCA-salt rats. Female Wistar rats were randomized in 3 groups: sham-operated, ovariectomized (OVX), and OVX plus hormone replacement with estradiol (E) or estradiol/progesterone (EP). Two weeks later, rats were uninephrectomized and further randomized in DOCA-salt (subcutaneous injections of desoxycorticosterone and drinking water containing NaCl/KCl) and control normotensive (subcutaneous injections of vehicle and tap water). Blood pressure was evaluated both by direct and standard tail-cuff methods. Responses to IRL-1620 were evaluated in vivo/in situ in the mesenteric microcirculation. mRNA expression of ET-1 and ET <jats:sub>A/B</jats:sub> receptors was evaluated in mesenteric arteries by reverse transcription–polymerase chain reaction and expressed relative to GAPDH. OVX-DOCA rats developed a more severe form of hypertension than did DOCA rats. Treatment with E or EP restored blood pressure to levels observed in DOCA rats. In the mesentery, IRL-1620 induced vasodilatation in control rats, a mild vasoconstriction in DOCA rats, and marked vasoconstriction in OVX-DOCA rats. Both E and EP decreased IRL-1620–induced vasoconstriction in the DOCA group. In the normotensive group, OVX did not change blood pressure or IRL-1620–induced vasodilation. Removal of the ovaries increased ET-1 mRNA in arteries from DOCA and control rats, although treatment with E or EP reversed these changes. Vascular ET <jats:sub>B</jats:sub> receptor mRNA levels were greatly enhanced in OVX-DOCA but not OVX-control rats. Hormone replacement with E or EP restored ET <jats:sub>B</jats:sub> receptor expression in the DOCA group. A greater blood pressure–lowering effect of bosentan (ET <jats:sub>A</jats:sub> /ET <jats:sub>B</jats:sub> blocker) was observed in OVX-DOCA rats. The observation that OVX worsens hypertension as well as the altered ET <jats:sub>B</jats:sub> receptor–mediated responses and the effects of bosentan in female DOCA rats supports our suggestion that the ovarian hormones modulate ET-1/ET <jats:sub>B</jats:sub> receptor vascular responses/expression in DOCA-salt hypertension. </jats:p>