Platelet-activating factor (PAF-acether), a phospholipid mediator involved in inflammatory reactions, has been reported to induce endovascular surface lesions. We investigated the possible involvement of PAF-acether in the mechanism of arterial cholesterol deposition. Rabbits fed a normal or hypercholesterolic diet were treated orally for 1 month with BN 52021 (20 mg/kg per day), a specific PAF-acether antagonist, and killed at the end of treatment. Cholesterol feeding resulted in a marked (50-fold) increase in plasma cholesterol. However, the drug had no significant effect on the diet-induced hypercholesterolemia. Free and esterified cholesterol were markedly increased (635%) in the aorta of animals receiving the atherogenic diet. This accumulation was reduced by 36% upon simultaneous administration of BN 52021 (P less than 0.02, n = 15). This decrease essentially affected the esterified cholesterol content. Conversely, BN 52021 showed no effect on the cellular cholesterol esterification, since liver acyl-CoA: cholesterol acyltransferase activity remained unchanged. This study indicates that BN 52021 is effective in reducing cholesterol accumulation in rabbit atherosclerotic aorta, without changing the plasma cholesterol levels.