Background: Vascular disease progresses more slowly in females with functional ovaries than in males. The mechanisms of this vasoprotective effect of female sex are incompletely understood. This study tested (1) whether there is a sex difference in the development of myointimal proliferation after balloon injury of the rat carotid artery in vivo, (2) whether this response is estrogen or androgen dependent, and (3) whether there is a sexual dimorphism in expression of the c-myc protooncogene in intact and/or damaged rat carotid arteries. Methods and Results: Ten-week- old male and female Sprague-Dawley rats were either gonadectomized or studied intact. Gonadectomized rats of both sexes were implanted with estradiol, testosterone, or nothing (control) 3 days before vascular injury. Two weeks later, the rats were killed by overdose of pentobarbital, and the injured right and uninjured control left carotid arteries were fixed and subjected to morphometric analysis for evaluation of the degree of myointimal thickening. Separate groups of intact male and female rats were hired at 1 and 2 hours after vascular injury, and total RNA from injured and uninjured vessels was subjected to Northern blot analysis for assessment of steady state c-myc mRNA levels. Neointimal area and the ratio of neointimal to medial area were significantly less in intact female rats than in intact male rats (P<.05). Gonadectomy of female rats was associated with a greater increase in neointima formation after balloon injury than that observed in intact females (P<.05), but testosterone replacement did not further enhance this response. Estradiol treatment significantly inhibited myointimal proliferation after vascular injury in gonadectomized rats of both sexes (P<.05). Neither gonadectomy nor gonadectomy plus testosterone replacement altered the myointimal proliferative response to balloon injury in male rats. Steady state c-myc mRNA levels were detectable in undamaged carotid arteries in intact rats of both sexes and were significantly greater in males than in females; c-myc mRNA levels were increased in both sexes after carotid injury, but the response was significantly larger in magnitude and more rapid in males than in females. Conclusions These data indicate that the sex difference in myointimal proliferation after vascular injury is estrogen dependent. C-myc gene expression is greater in the undamaged carotid artery of the male than in that of the female, and the responsiveness of this gene to balloon injury of the artery is more rapid and more robust in the male than in the female rat. These findings have direct implications for the prevention and treatment of vascular disease in humans.