Aspirin has potent antiinflammatory properties and attenuates atherosclerosis in apolipoprotein-E-deficient mice fed a high-fat, high-cholesterol diet. In an attempt to clarify the contradictory results obtained with normal chow, we studied the effect of aspirin for a prolonged period of time. The mice were fed a commercial chow until the experiment began at 8 weeks of age. Blood samples were then obtained and several mice (n=8) were sacrificed. The diet of the remaining 48 animals was supplemented with 200 g/kg palm fat and 1 g/kg cholesterol. They were then randomly divided into 2 groups, one of which received 0.5 mg/day of aspirin. The aspirin had a time-dependent effect. First, the extent of lesion decreased; then the effect was neutral; and, finally, after longer periods of being fed the atherogenic diet and receiving aspirin, the extent of the lesion increased. The transitory effect of aspirin should be elucidated in the absence of high dietary lipids.