To investigate the effect of estrogen (E) on vascular apoptosis during atherosclerotic plaque formation.Laboratory study using a murine atherosclerosis model.Academic research center.Female mice homozygous for null alleles of LDL receptor (LDL-R −/− ) in a C57BL/6 background. LDL-R −/− mice develop atherosclerosis in a predictable manner when fed a high cholesterol diet.Eight-week-old female LDL-R −/− mice (n = 68) were ovariectomized, and implanted subcutaneously with 90-day release pellets containing 0.5 mg of 17β-estradiol (E 2 ) or placebo. Four animals were evaluated at the initiation of the study. Thereafter, four animals from each group were sacrificed weekly for 8 weeks and their aortas studied.The effect of E 2 on atherosclerotic plaque development, apoptosis, and cell proliferation was examined in the aorta of ovariectomized LDL-R −/− mice that were fed a high cholesterol diet.Mice treated with E 2 displayed a delay in atherosclerotic plaque formation, associated with an increase in DNA strand breaks in the arterial wall indicative of increased apoptosis, compared to placebo-treated mice. The two groups did not differ in mitotic activity.In female LDL-R −/− mice fed a high cholesterol diet, ovariectomy is associated with increased atherogenesis. The effect of ovariectomy on atherogenesis is reversed by E 2 treatment. In addition to delayed atherogenesis, E 2 treatment of ovariectomized LDL-R −/− mice results in an increase in apoptosis in the aortic wall without an effect on the mitotic activity. Our findings suggest that vascular effects of E may be in part mediated by a proapoptotic activity.