Anti-atheromatous effects of fenofibrate were studied in cholesterol-fed rabbits. Rabbits in the control group (HCD) and fenofibrate group (F-HCD) were fed the 0.5% cholesterol diet and the 0.5% cholesterol plus 0.11% fenofibrate diet (corresponding to ca. 30 mg/kg/day), respectively, for 2, 4 or 10 weeks. Fenofibrate did not change serum levels of total cholesterol, HDL-cholesterol and triglyceride during the feeding period. The percentage of plaque area (PPA) formation in the thoracic aorta was time-dependently increased. PPA values were reduced in the rabbits treated with fenofibrate for 2 and 4 weeks, but not in those treated for 10 weeks. Fenofibrate had no effect on the plaque thickness. The percentage of circulating free platelets in the HCD group was reduced at the 4th week of feeding, but that in the F-HCD group was not. The anti-platelet effect of fenofibrate might cause the anti-atheromatous effect. Fenofibric acid, an active metabolite of fenofibrate, had no inhibitory effect on LDL peroxidation in vitro. From these results, we conclude that fenofibrate manifests an anti-atheromatous effect independent of the hypolipidemic effect in cholesterol-fed rabbits and that it may inhibit an early event in the atherogenesis.