Liver allograft cirrhosis is a relatively uncommon complication of liver transplantation. Most cases can be attributed to disease recurrence, particularly recurrent hepatitis C. Little is known about the frequency, etiology, and natural history of liver allograft cirrhosis occurring without evidence of recurrent disease. The aim of the present study was to review the clinicopathological features in this group of patients. We retrospectively reviewed data from all adult patients who were transplanted between 1982 and 2002 and survived >12 months after orthotopic liver transplantation (n = 1,287). Cases of histologically proven cirrhosis were identified from histopathological data entered into the Liver Unit Database. A total of 48 patients (3.7%) developed cirrhosis. In 29 of them, cirrhosis could be attributed to recurrent disease (hepatitis C, 11; hepatitis B, 4; autoimmune hepatitis, 4; primary biliary cirrhosis, 2; primary sclerosing cholangitis, 3; nonalcoholic steatohepatitis, 4; alcoholic liver disease, 1). In 9 of the 19 patients without evidence of disease recurrence, another cause of cirrhosis could be identified (de novo autoimmune hepatitis, 4; biliary complications, 4; acquired hepatitis B, 1). In the remaining 10 cases, the cause of cirrhosis remained unknown; their previous biopsies had shown features of chronic hepatitis of uncertain etiology. Three patients in this group died, and the remaining 7 are alive with good graft function 3-12 years after cirrhosis was first diagnosed. The prevalence of "cryptogenic" posttransplant cirrhosis was significantly higher in patients initially transplanted for fulminant seronegative hepatitis (6%) than in those transplanted for other diseases (0.3%). In conclusion, posttransplant cirrhosis without disease recurrence is uncommon, but it is more frequent in patients transplanted for fulminant seronegative hepatitis. Chronic hepatitis is the most frequent underlying pathological process in cases where the cause of cirrhosis remains uncertain.