We report on 56 children with sclerosing cholangitis (SC) seen between 1972 and 1992. The first symptoms occurred at a mean age of 3.7 years; 15 infants had neonatal cholestatic jaundice. At diagnosis, cholestatic jaundice was present in 25 children, hepatomegaly in 54, splenomegaly in 41, and ascites in 12. Serum alkaline phosphatase activity was increased in 49 patients and gamma-glutamyltransferase activity in all patients tested. Most often the histopathologic findings were extensive portal fibrosis and neoductular proliferation. Cholangiography showed abnormal intrahepatic bile ducts in all children and abnormal extrahepatic bile ducts in 35 (63%). The children were separated into three groups: (1) those with SC of neonatal onset (27%); (2) those with SC of postneonatal onset associated with another disease (55%)--histiocytosis X in 14 children, immunodeficiency syndromes in 8, chronic inflammatory bowel disease or autoimmune hepatitis in 8, and congenital psoriasis in 1; and (3) those with SC of postneonatal onset without an associated disease (18%). Biliary cirrhosis was present in all but three children after 6 months to 19.3 years of follow-up. Eleven children died of portal hypertension or liver failure, and six died of a complication related to the associated disease. Fifteen children had liver transplantation; 11 of these are alive 6 months to 6 1/2 years later without recurrence of SC. The overall estimated median survival time of children with SC was 10 years from clinical onset. These results indicate that SC should be suspected in all children with a chronic cholestatic disease and increased serum gamma-glutamyl transferase activity, especially when diseases known to be associated with SC are present. The prognosis is poor, but liver transplantation should be considered except in those with severe immunodeficiency syndromes.