The short term effects of fenofibrate (150 mg/kg per day), administered by gavage, on lipoprotein and fatty acid distribution have been investigated in an hypertriglyceridemic model, the Zucker rat. Lean rats were compared to control obese and treated obese rats, and control obese animals to treated obese littermates. Classically, plasma cholesterol and triacylglycerol increased by 1.8- and 7.9-fold, respectively, in control obese versus lean rats. Treatment of the Zucker obese rats with fenofibrate reduced their plasma cholesterol by 10% and raised triacylglycerol by 47% (P less than 0.001) in comparison to untreated control obese rats. These effects were accompanied by a change in the composition of all plasma lipoproteins. The cholesterol/triacylglycerol ratio in VLDL rose by 32% while that in LDL and HDL fell by 43 and 47%, respectively. Drug therapy altered the fatty acid profile in both plasma and liver; the percentage of polyunsaturated fatty acids fell while monounsaturated fatty acids increased. The increased proportion of monounsaturated fatty acids in plasma suggests that the fatty acid composition of circulating lipoproteins is modified, particularly in VLDL. This, in association with the altered lipid distribution in VLDL may reflect an abnormal metabolism of this lipoprotein. In view of these abnormalities, we conclude that this rat is not an appropriate model for the short-term study of clofibrate analogues.