Background and Objectives Fibrates induce hepatic peroxisome proliferation and carcinogenesis in rodents by activating peroxisome proliferator‐activated receptor α (PPARα). There is no conclusive evidence that humans are unresponsive to peroxisome proliferation, and concern exists about the long‐term safety of fibrate treatment. Methods In a university hospital setting, 48 patients with uncomplicated gallstones and a serum level of low‐density lipoprotein cholesterol greater than 130 mg/dL were randomly assigned to open‐label treatment with bezafibrate (400 mg/d), fenofibrate (200 mg/d), gemfibrozil (900 mg/d), or placebo for 8 weeks before elective cholecystectomy. Serum samples for lipid determinations were obtained at baseline and before surgery. A liver specimen was obtained at operation, and the relative levels of messenger ribonucleic acid (mRNA) for the wild and truncated forms of PPARα, acyl coenzyme A oxidase, liver carnitine palmitoyltransferase I, apolipoprotein A‐I, and stearoyl coenzyme A desaturase were determined. Results Fenofibrate, bezafibrate, and gemfibrozil reduced plasma low‐density lipoprotein cholesterol levels by 22% (P = .009), 14% (P = .042), and 11% (not significant), respectively. Plasma triglyceride levels decreased significantly (24%‐36%; P < .05), whereas high‐density lipoprotein cholesterol levels rose nonsignificantly after treatment with the 3 fibrates. Except for a 35% increase of apolipoprotein A‐I mRNA after fenofibrate administration (P < .05), none of the individual fibrates induced significant changes in the mRNAs tested, although as a group they increased the mRNA for liver carnitine palmitoyltransferase I by 40%(P = .08; marginally significant). Conclusions Fibrate administration to humans at pharmacologic doses able to activate PPARα and to induce a hypolipidemic effect does not increase the hepatic expression of acyl coenzyme A oxidase, a well‐known marker of peroxisome proliferation in rodents. Clinical Pharmacology & Therapeutics (2002) 72, 692–701; doi: 10.1067/mcp.2002.128605