Squalene is an obligate intermediate of cholesterol synthesis and plasma squalene to cholesterol ratio correlates significantly with cholesterol synthesis rate in the liver. Sixteen nonobese patients with radiolucent gallstones were randomly allocated into two treatment groups receiving 15 mg/kg/day ursodeoxycholic acid (group A) or 15 mg/kg/day lactose (group B) administered three times daily for 30 days. In group A, biliary squalene to cholesterol ratio was significantly lowered (from 1.19 to 0.86, P less than 0.02), as was cholesterol saturation (from 1.39 to 0.95, P less than 0.001); levels of plasma very-low-density lipoprotein cholesterol (VLDL-C) (from 30 to 26 mg/dL) and plasma VLDL-triglyceride (VLDL-TG) (from 81 to 68 mg/dL) decreased significantly only in the group taking ursodeoxycholic acid. No variations of squalene concentrations and squalene to cholesterol ratio were observed in the plasma of both groups. Biliary cholesterol saturation during ursodeoxycholic acid administration correlated directly with squalene to cholesterol ratio in bile; reduction of these two parameters is accompanied by decreased VLDL-C levels.