No effective medical therapy is available for patients with primary sclerosing cholangitis (PSC). We evaluated the safety and estimated the efficacy of silymarin in patients with PSC in a pilot study. Thirty patients with PSC were enrolled. Silymarin, 140 mg orally three times daily, was given for 1 year. A statistically significant improvement in serum alkaline phosphatase activity (1131 ± 216 vs. 861 ± 139, P = 0.007), and aspartate aminotransferase (AST) levels (116 ± 15 vs. 83 ± 11, P = 0.01) occurred with treatment. Serum bilirubin levels were not significantly affected by the treatment, while serum albumin and the Mayo risk score remained essentially unchanged. Overall, 34% of patients had a positive response to silymarin as defined by %ge;50% improvement or normal status in liver tests. The results of this pilot study warrant further evaluation of silymarin in patients with PSC in a large-scale, controlled trial.