One hundred renal transplant recipients were studied for antibodies to hepatitis C virus (HCV), and to HCV RNA in serum by reverse transcription+nested polymerase chain reaction (RT-PCR). Presence of antibody to HCV confirmed by recombinant immunoblot assay II was considered evidence of HCV infection, and detection of HCV RNA by RT-PCR was considered evidence for active viremia. On pretransplant sera, 18 patients were RT-PCR positive and an additional 3 had antibody evidence of HCV infection. At 1-year follow-up, all of these patients were RT-PCR positive and an additional 7 patients became RT-PCR positive. Clinical diagnosis of non-A, non-B hepatitis underestimated the prevalence of HCV infection (5/28 cases, 18%). Serum alanine aminotransferase (ALT) elevations were neither sensitive nor specific. An isolated pretransplant ALT elevation predicted a 52% chance of being RT-PCR positive for HCV. An ALT elevation greater than 2 months after transplant predicted a 45% chance of HCV positivity; however, 18% of patients who never had any ALT abnormality were also HCV positive. Sixty-eight patients had an early postoperative rise in ALT, but there was no correlation with HCV status. After an average follow-up of over 4 years, 3/28 HCV-positive patients developed cirrhosis. HCV infection in the renal transplant population is common and underdiagnosed by clinical and biochemical parameters. HCV appears not to cause aggressive liver disease in the early posttransplant period, but longer follow-up is needed to define the natural history of HCV in the renal transplant population.