GOALS/BACKGROUND: Diagnosis, treatment, and prognosis of the overlap syndrome of autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are controversial. Our aim was to assess the clinical characteristics and long-term prognosis of the AIH/PSC overlap syndrome. STUDY: We reviewed the data of 16 patients seen in our center who fulfilled the diagnostic criteria of both diseases at some stage of their medical history. RESULTS: All patients had initially presented with laboratory markers of both, cholestasis and definite AIH. Histologic reexamination of initial biopsies, available from 11 of 16 patients, revealed features of both AIH and PSC in all biopsies. Cholangiography was performed at initial presentation in 9 of 16 patients and appeared normal in 6 of 9 patients. During follow-up cholangiography, an additional 11 patients developed pathologic characteristics of PSC. The age and sex distribution was typical for PSC. Immunosuppressive therapy improved biochemical markers; however, fibrosis was observed to progress in all patients during a median observation period of 12 years. Three patients initially presented with cirrhosis, 12 of 16 patients developed cirrhosis at the end of the observation period, and 3 developed complications of cirrhosis. CONCLUSIONS: Overlap of AIH and PSC was detected most reliably on grounds of serologic markers and histology; early bile duct changes were often missed by endoscopic retrograde cholangiography. Immunosuppression combined with ursodeoxycholic acid seems to be beneficial, but cannot prevent long-term progression toward cirrhosis in the majority of patients.