Estrogens protect against cardiovascular disease in women through effects on the vascular wall and liver. Here we further characterize the rat as a model for the evaluation of estrogenic effects on plasma lipid levels vs. uterine wet weight. In adult ovariectomized female rats treated for 4 days s.c., 17alpha-ethinyl estradiol (EE) was the most potent agent to lower plasma total and high density lipoprotein cholesterol levels, followed by 17beta-estradiol and 17alpha-estradiol. However, 17alpha-estradiol had the greatest separation of uterotropic vs. cholesterol-lowering effects. EE had the same lipid-lowering potency whether administered s.c. or orally to adult rats. It had no effect on cholesterol levels in immature rats, even though the uterotropic response was dramatic. Testosterone propionate, dexamethasone, and progesterone did not significantly lower cholesterol levels. The antiestrogens tamoxifen and raloxifene lowered cholesterol levels, but with less efficacy and potency than the estrogens. ICI 182780 had no effect on cholesterol levels. When coadministered with EE, ICI 182780 inhibited the cholesterol-lowering and uterotropic activities of EE, suggesting that the estrogen receptor pathway is involved. In conclusion, although the information from the rat is limited as a model of the low density lipoprotein-lowering effects of estrogens in humans, it can be used to study the effects and mechanism of action of estrogen and antiestrogens on plasma cholesterol levels.