Primary sclerosing cholangitis is a progressive, ultimately fatal, chronic hepatobiliary disorder for which no effective medical or surgical therapy now exists. The syndrome occurs most commonly in young men and is characterized by a chronic cholestatic syndrome, frequent association with chronic ulcerative colitis, hepatic copper overload, a paucity of serologic markers, and characteristic abnormalities in some liver-biopsy specimens and most cholangiograms. The natural history of the syndrome is unclear; the disease is likely to progress slowly and relentlessly, over a decade or longer, from an asymptomatic stage to a condition characterized by symptoms of cholestasis and complicated by cirrhosis, portal hypertension, and possibly carcinoma of the bile ducts. Screening techniques based on automated biochemical analyses are likely to lead to a diagnosis of primary sclerosing cholangitis in increasing numbers of patients, perhaps in the early, preicteric stage. An increased level of serum alkaline phosphatase in a young man, particularly if he has chronic ulcerative colitis, should strongly suggest the presence of this syndrome and the need for additional diagnostic studies. Endoscopic retrograde cholangiography and liver biopsy should be considered under these circumstances.