Cholangiocarcinoma is more likely to develop in patients with primary sclerosing cholangitis. Our aims were to describe the clinical presentation, course, and management of patients afflicted with both cholangiocarcinoma and primary sclerosing cholangitis and to estimate the prevalence of cholangiocarcinoma in patients with primary sclerosing cholangitis. A retrospective analysis was conducted of 30 patients with both primary sclerosing cholangitis and cholangiocarcinoma managed at our institution during an 8-year period. Development of cholangiocarcinoma was heralded by rapid clinical deterioration with jaundice, weight loss, and abdominal discomfort. Cholangiocarcinoma complicating primary sclerosing cholangitis often was detected at an advanced tumor stage, which precluded effective therapy, and overall median survival was 5 months. Earlier recognition and treatment of cholangiocarcinoma in such patients will be necessary to increase survival rates. Seventy patients with primary sclerosing cholangitis were followed prospectively in a clinical trial of medical therapy for an average of 30 months. Twelve patients died and five were found at autopsy to have cholangiocarcinoma. The potential for cholangiocarcinoma to develop in patients with primary sclerosing cholangitis may indicate that liver transplantation should be considered earlier in the course of the disease.