In humans, clofibrate increases the degree of bile cholesterol saturation and predisposes patients to cholesterol gallstone formation. To determine if this activity extends to the related hypolipidemic agent fenofibrate, duodenal bile lipid composition was studied in 15 subjects before they participated in a double-blind study of that drug. Eight subjects were studied again on fenofibrate and six on placebo; five placebo patients were also studied later on open-label fenofibrate. The results were similar in the double-blind and open-label studies, and changes in bile lipid composition were comparable to those seen in studies of clofibrate. Fenofibrate caused a significant decrease in the molar percentage of bile acids and increases in the molar percentage of phospholipids and cholesterol. The changes in bile acids and phospholipids had opposing effects on the cholesterol-holding capacity of bile. A statistically significant increase in the cholesterol saturation index was only apparent when all fenofibrate bile analyses were compared with all untreated bile analyses. The results demonstrated that fenofibrate has clear effects on bile lipid composition that may be associated with an increased propensity for gallstone formation, and when fenofibrate is used, patients should be monitored for this possibility.