Background: Estrogen blunts the neointimal response to vascular injury in gonadectomized rats of both sexes; addition of a progestin blocks the estrogen effect. This study tested, in intact rats of both sexes, whether (1) exogenous estrogen has a vasoprotective effect in injured carotid arteries, (2) progestin (medroxyprogesterone acetate, MPA) blocks the vasoprotective effect of estrogen, and (3) any observed sexual dimorphism in the responses to estrogen and/or MPA can be accounted for by differences in serum 17β-estradiol levels. Methods and Results: Intact male and female Sprague-Dawley rats were randomly divided into four subgroups treated with either (1) 17β-estradiol (2) MPA, (3) 17β-estradiol+MPA, or (4) vehicle and were subjected to balloon injury of the right common carotid artery. Two weeks later, rats were killed by an overdose of pentobarbital, and the carotid arteries were evaluated for myointimal thickening. Neither estradiol nor MPA altered the neointimal response in males. In females, estradiol reduced and MPA enhanced the response, whereas addition of MPA to estradiol blocked the vasoprotective effects of estrogen. Conclusions: Intact male rats but nut intact females are resistant to the vasoprotective effects of exogenous estrogen, despite attainment of physiological (for females) serum 17β-estradiol levels, MPA enhances the neointimal response in intact females, presumably by blocking the production and thus the vasoprotective effect of endogenous estrogen.