We studied the effects of a synthetic adrenocortical steroid, dexamethasone, on the development of experimental atherosclerosis in cholesterol-fed rabbits. Daily intramuscular injection of dexamethasone (0.125 mg/day) remarkably inhibited the aortic atherosclerosis induced by feeding a 1% cholesterol-rich diet for 8 weeks, although it aggravated diet-induced hyperlipidemia. Histologically, less foam cell accumulation was observed in the atherosclerotic lesions of the dexamethasone-treated rabbits as compared with the control animals. When rabbits were fed a normal chow diet for 10 weeks after receiving the 1% cholesterol-rich diet for 8 weeks, no regression of atherosclerotic lesions was observed with the daily injection of dexamethasone (0.125 mg/day); however, the drug again tended to inhibit further progression of atherosclerosis. The anti-atherogenic mechanism of dexamethasone may involve an inhibition of recruitment of blood monocytes and the insudation of atherogenic lipoproteins, mainly beta-very low density lipoprotein (beta-VLDL) in the present experiments, into the aortic intima, or it may involve a change in the size and structure of the lipoproteins, resulting in their decreased passage through the aortic endothelium into the intima.