Administration of moderate pharmacological doses of oestrogen to cholesterol-fed rabbits for 12 weeks resulted in a dramatically retarded development of arterial lesions as compared to non-oestrogen-treated, cholesterol-fed rabbits (7% vs. 47% aortal involvement). Oestrogen treatment was associated with a retarded increase in plasma cholesterol, and five times higher high density lipoprotein (HDL) to very low density lipoprotein (VLDL) cholesterol ratio. Expression of hepatic lipoprotein receptor activity, as detected by heparin-releasable binding of 125I-hypercholesterolaemic VLDL, was heavily suppressed by cholesterol feeding. Administration of oestrogen modulated this response and resulted in higher receptor expression. In accordance, oestrogen treatment resulted in a less prominent reduction of 125I-hypercholesterolaemic VLDL clearance in the cholesterol-fed rabbits. VLDL from both groups of cholesterol-fed animals stimulated cholesteryl ester synthesis in cultured macrophages to the same extent. Thus, in rabbits under a dietary cholesterol load, oestrogen counteracted hepatic lipoprotein receptor suppression, reduced plasma VLDL- and increased plasma HDL-cholesterol levels, and to a large extent abolished the development of atherosclerosis.