The mechanisms of the lipid-lowering agent gemfibrozil on biliary lipid metabolism were studied in eight normolipemic male volunteers. These measurements were performed before and after 3 months of administration. During administration of gemfibrozil, plasma cholesterol decreased by 19% (P less than 0.01) and triglycerides by 46% (P less than 0.01), and HDL cholesterol increased by 10% (P less than 0.01). The lithogenic index in gallbladder bile increased from 0.73 to 1.37 (P less than 0.05) and in hepatic bile from 0.86 to 1.42 (P less than 0.01). The increase in lithogenicity of gallbladder bile and hepatic bile was due to an increased biliary output of cholesterol from 47 to 70 mg/h (P less than 0.01) and a decreased output of bile acids from 943 to 694 mg/hr (P less than 0.01), whereas phospholipid output was not altered. The reduction in bile acid output was a result of a significant decrease in chenodeoxycholic acid secretion (r = 0.852; P less than 0.01). Cholic acid output was not affected by gemfibrozil. These results suggest that administration of gemfibrozil enhances the possible risk of gallstone formation like clofibrate.