The influence of the peroxisomal proliferators perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid on lipid metabolism in rats was studied. Dietary treatment of male Wistar rats with these three compounds resulted in rapid and pronounced reduction in both cholesterol and triacylglycerols in serum. The concentration of liver triacylglycerols was increased by about 300% by PFOSA. Free cholesterol was increased by both perfluoro compounds. Cholesteryl ester was reduced to 50% by PFOSA as well by clofibrate. In hepatocytes from fed rats, all the compounds resulted in reduced cholesterol synthesis from acetate, pyruvate and hydroxymethyl glutarate, but there was no reduction of synthesis from mevalonic acid. The oxidation of palmitate was also increased in all groups. The perfluoro compounds, but not clofibrate, caused some reduction in fatty acid synthesis. The activity of liver HMG-CoA reductase was reduced to 50% or less in all treatment groups and all three compounds led to lower activity of acyl-CoA:cholesterol acyltransferase (ACAT). Changes in other enzymes related to lipid metabolism were inconsistent. The present data suggest that the hypolipemic effect of these compounds may, at least partly, be mediated via a common mechanism; impaired production of lipoprotein particles due to reduced synthesis and esterification of cholesterol together with enhanced oxidation of fatty acids in the liver.