Cardiovascular disease is a major killer in postmenopausal women in the industrialized societies. To investigate the effect of progestogen and 17 beta-estradiol replacement therapy on atherogenesis, we studied 60 cholesterol-fed ovariectomized rabbits for 13 weeks. They were randomly assigned to four groups of 15 rabbits each and received oral treatment with norethisterone acetate, levonorgestrel, 17 beta-estradiol, or placebo. The active treatment groups achieved serum hormone concentrations, which produced physiological effects on the uterus. No significant differences in serum total cholesterol or ultracentrifuged lipoproteins (very low density, intermediate density, low density, or high density lipoproteins) were found between the four groups during the experimental period. There were no significant differences between the progestogen and placebo groups in the aortic accumulation of cholesterol. The estradiol group had only accumulated about half the aortic cholesterol as compared with the placebo group and the progestogen groups (p less than 0.05). The antiatherogenic effect of 17 beta-estradiol was estimated to be equal to a 40-50% reduction in serum total cholesterol. These findings suggest that two commonly prescribed 19-nortestosterone-derived progestogens, which are considered to be "atherogenic," do not affect atherogenesis in cholesterol-fed ovariectomized rabbits, whereas 17 beta-estradiol produces a significant antiatherogenic effect that is independent of lipid metabolism in plasma, possibly the result of a direct action on the arterial wall.