These studies examine the effects of a hypercholesterolemic diet (with butter and cholesterol added), or a hypertriglyceridemic diet (30% sucrose (w/v) in drinking water), on murine plasma lipids and lipoproteins prepared either by sequential ultracentrifugation or gel exclusion chromatography. The hypercholesterolemic diet increased plasma cholesterol (186%), particularly that associated with very low (VLDL) and low (LDL) density lipoproteins. In addition, the cholesterol/triglyceride ratio in the VLDL fraction rose significantly from 0.10 to 4.0. The hypertriglyceridemic diet raised markedly plasma triglyceride levels (46%) by expanding the circulating VLDL pool (+39%). These dietary modifications were used to provide a model for the examination of 3 classical hypolipidemic drugs (fenofibrate, gemfibrozil and nicotinic acid). In animals receiving the standard diet, fenofibrate, gemfibrozil and nicotinic acid decreased the triglyceride (TG) level (-28%, -31%, and -38%) by lowering VLDL-TG (-37%, -42%, and -49%), fenofibrate and gemfibrozil increased HDL-cholesterol by 18% and 31%, respectively. In animals receiving the hypercholesterolemic diet fenofibrate lowered the total plasma cholesterol level by 40%, at the same time increasing HDL-cholesterol by 23%. In animals fed sucrose, on the other hand, fenofibrate (100 mg/kg per day) and nicotinic acid (900 and 600 mg/kg per day) reduced plasma triglyceride levels (-20%, -40% and -33%), and nicotinic acid (900 mg/kg per day) decreased VLDL-TG by 58%. These results are in good agreement with clinical data from studies in man and suggest that this animal model may provide a useful and rapid screening system for testing new lipid lowering drugs.