Clinical course and serial liver histology of a patient who developed fatal chronic active hepatitis C after renal transplantation are presented. This patient developed persistently deranged liver biochemistry 3 months after transplantation, despite normal liver enzyme values during the preceding 3 years on hemodialysis. In addition to increased parenchymal enzyme concentrations, the levels of ductal enzymes were also markedly elevated, with peak levels of alanine aminotransferase and gamma-glutamyl transpeptidase 7 and 100 times, respectively, the normal upper limit. The patient was persistently seronegative for hepatitis C virus (HCV) antibodies, but positive for HCV RNA. Treatment with alpha-interferon for 6 months, initiated after the development of early cirrhosis, resulted in no improvement, and the patient died from liver failure 36 months after renal transplantation. Serial liver histology, examined four times from 11 months to 36 months after transplantation, showed progressive deterioration from chronic active hepatitis to cirrhosis. This patient illustrates the uncommon complication of rapidly progressive and ultimately fatal liver disease due to HCV infection after renal transplantation. Early recognition with anti-HCV and HCV RNA assays as well as histologic assessment are crucial for the identification of patients with a poor prognosis who might benefit from therapeutic intervention before irreversible liver damage.