Cholangiocarcinoma remains difficult to diagnose and is a major cause of death in patients with primary sclerosing cholangitis. Recently serum carcinoembryonic antigen and carbohydrate antigen 19-9 (CA 19-9) levels have been reported to improve diagnostic accuracy in patients with cholangiocarcinoma and primary sclerosing cholangitis. We reviewed our experience with cholangiocarcinoma complicating primary sclerosing cholangitis to identify clinical factors associated with cholangiocarcinoma in patients with primary sclerosing cholangitis and to determine the appropriate management of patients with confirmed or suspected cholangiocarcinoma. Between 1984 and 1997, 25 patients (18%) were diagnosed with cholangiocarcinoma among 139 patients with primary sclerosing cholangitis. The diagnosis of primary sclerosing cholangitis was made coincident with the diagnosis of cholangiocarcinoma in 12 patients and preceded it by a mean of 62 months in the remaining 13 patients. The incidence of inflammatory bowel disease was higher (P <0.05) in patients with cholangiocarcinoma (80% vs. 61%). Nine patients (36%) with cholangiocarcinoma were managed with either extrahepatic bile duct resection and/or partial hepatic resection (n = 5) or liver transplantation (n = 4), and the remaining 16 patients were unresectable at presentation. Serum CA 19-9 was elevated in all six patients with cholangiocarcinoma who were analyzed and in none of the eight patients without cholangiocarcinoma who were tested (P <0.01). Actuarial 1- and 3-year survival rates in the resected patients (56% and 28%, respectively) were significantly longer (P <0. 02) than in the unresected patients (13% and 0%, respectively). The 10-year actuarial mortality rates for cholangiocarcinoma among all 139 patients was 25%. In summary, cholangiocarcinoma was the leading cause of death in patients with primary sclerosing cholangitis and was often diagnosed concurrently with or within months of its diagnosis. Early liver transplantation for patients with primary sclerosing cholangitis will not reduce the incidence of cholangiocarcinoma-related mortality in these patients.