Abstract 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 14C-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.