This study examines the clinical and pathologic course of seven patients who developed giant cell hepatitis (GCH) after liver transplantation. Five of these patients also had GCH as their native liver disease and experienced a particularly aggressive course because of recurrent disease, beginning 1-21 months after transplantation. Two died and another two required hepatic retransplantation because of recurrent GCH; one of them had GCH recurrence in a second liver allograft. A remaining patient with recurrent GCH is alive 6 years after transplantation. Follow-up of the two patients who developed de novo GCH between 8 and 24 months after hepatic transplantation showed active micronodular cirrhosis in one and persistent giant cell transformation in the other at 4 years. All of the patients were serologically negative for hepatitis C virus, hepatitis B virus, and human immunodeficiency virus before transplantation. One patient became positive for hepatitis C virus after transplantation. Two patients had an associated autoimmune syndrome, which could have been accounted for by the GCH. None had a history of drug exposure. Interestingly, human papilloma virus (HPV) type 6 was detected by PCR analysis of liver tissues with GCH from one of three cases before and three of four cases after transplantation. This small series shows that GCH occurs in liver allografts, but it is uncommon. Documentation of recurrent disease in five of seven patients suggests that GCH in a subgroup of patients may be related to a transmissible agent, or that a particular recipient may injure livers in a way that elicits a giant cell reaction.