In vitro data suggests that lifibrol lowers plasma cholesterol by inhibiting cholesterol synthesis. We report that lifibrol is far less potent in vitro and in vivo than lovastatin for inhibiting 14 C-acetate incorporation into sterols. Moreover, several major differences between lifobrol and lovastatin were noted in various animal models. In contrast, lifibrol exhibited several activities in common with gemfibrozil, another phenoxy-acid-type drug. Specifically, in normal rats lifibrol, like gemfibrozil, lowered plasma non- HDL-cholesterol and triglycerides, and increased liver weight and hepatic peroxisomal marker enzyme activities. Lovastatin only lowered plasma triglycerides. In cholesterol-fed rats lifibrol and gemfibrozil lowered non-HDL-cholesterol and elevated HDL-cholesterol while lovastatin was inactive. Finally, lovastatin but not lifibrol exhibited hypocholesterolemic activity in normal guinea pigs and resin-primed dogs. Our interpretation is that these data do not support the notion that lifibrol lowers plasma cholesterol in vivo by inhibiting cholesterol synthesis.