OBJECTIVE: To study the effects of ursodeoxycholic acid (UDCA) on lipid levels in patients with primary biliary cirrhosis (PBC). DESIGN: A randomized, placebo-controlled prospective trial of UDCA was conducted in 177 well-characterized patients with PBC. MATERIAL AND METHODS: The two treatment groups (placebo and UDCA) were matched at entry with respect to age, sex, histologic stage of PBC, biochemical values, and serum lipid levels. Serum cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were measured at entry, 1 year, and 2 years. RESULTS: The decrease in total cholesterol level at 1 and 2 years in the UDCA-treated group was significant in comparison with that in the placebo group. Serum high-density lipoprotein cholesterol and triglyceride levels, however, were unchanged. No severe side effects from UDCA were noted. The changes in serum cholesterol levels at 2 years were directly and strongly correlated with changes in serum bilirubin concentrations (r = 0.70; P < 0.001) and inversely correlated with initial serum cholesterol levels (r = -0.86; P < 0.00001). CONCLUSION: The cholesterol-lowering effect of UDCA could be related to amelioration of the underlying liver disease or to a direct effect of the drug on the metabolism of cholesterol in patients with hypercholesterolemia.