Introduction As discussed in companion articles in CLD, the clinical course of large duct primary sclerosing cholangitis (PSC) is highly variable and unpredictable. Although the median survival from presentation to death or liver transplantation in symptomatic patients is approximately 10-12 years, 75% of asymptomatic patients will survive 15 years or more. A recent Dutch study has shown an overall median survival of 22 years in PSC patients. In the past, a majority of patients have died of hepatic failure following deepening, cholestatic jaundice. However, with the advent of successful transplantation, the majority of patients with large duct PSC die of hepatobiliary malignancy (cholangiocarcinoma (CCA), gall bladder cancer, or hepatoma in cirrhosis patients) or colonic adenocarcinoma (Fig. 1). One study has suggested an increase in the risk of pancreatic adenocarcinoma in PSC, but this has not been confirmed. However, it is apparent that despite an association with nonsmoking, large duct PSC is a premalignant disease. In contrast, small duct PSC has not been associated with an increased risk of either biliary or colonic neoplasia and has a much better prognosis.