Two artificial estrogens, ethinyl estradiol and mestranol, were found to cause cirrhosis in the rabbit liver during a study of atherosclerosis. These drugs showed protective effects against atherosclerosis in cholesterol-fed rabbits when administered orally (1 ppm in diet). These drugs and two naturally occurring estrogens, estrone and estradiol, were similarly effective when administered intramuscularly (1.5 mg per rabbit per week) to rabbits fed a diet lower in cholesterol. Reduction by estrogens of plasma cholesterol did not fully account for the reduction of extent of aortic atherosclerosis. Also, no differences in aortic or platelet eicosanoid production from exogenous arachidonic acid were found to explain the effect on atherogenesis. The 2 artificially modified estrogens, ethinyl estradiol and mestranol, caused portal fibrosis with biliary proliferation (even in rabbits not fed cholesterol). Estrone, estradiol, and testosterone were not injurious in this regard at the dosages used. Only the unmodified estrogens reduced atherosclerosis without damaging the rabbit liver.