Alagille's syndrome is a common form of familial intrahepatic cholestasis. In addition to the hepatobiliary system, many other organ systems are affected. Most of the affected patients survive through adulthood. Hepatic involvement is the cause of death in about one-third of patients. Hepatocellular carcinoma complicating the course of this disease is very rare and has been reported previously in only three cases. We report a family in which three of four siblings with this syndrome developed hepatocellular carcinoma and died as a result of it. None of these children had a liver disease, other than Alagille's syndrome, that could account for the development of such a tumor. This experience suggests that Alagille's syndrome, or at least chronic cholestasis, may be a predisposing factor for the development of hepatocellular carcinoma. Annual determination of alpha-fetoprotein and abdominal computed tomography (CT) scan may detect the development of a hepatocellular carcinoma in such cases while they are still resectable.