We analyzed the long-term clinical course of 71 patients with RNA-positive hepatitis C virus (HCV) infection after liver transplantation. Patients with reinfection after transplantation for HCV-related liver disease, or de novo infection at transplantation were followed for up to 12 years. Cumulative survival for patients with HCV infection at 2, 5, and 10 years after transplantation was 67%, 62%, and 62%, respectively. It was not significantly different from that in patients transplanted for other nonmalignant diseases without HCV infection. The main factor determining long-term survival was the presence or absence of hepatocellular carcinoma (HCC) at transplantation. The 5-year survival rate for HCV patients with or without HCC was 35% versus 73%, respectively (P < .05). No deaths because of viral hepatitis of the graft were observed. Deaths in the first year after transplantation were caused by infectious complications, cardiovascular problems, or rejection; deaths after more than 12 months were exclusively because of recurrence of HCC. Biochemical and histological evidence of hepatitis was found in the majority of the patients, only 16% had normal alanine aminotransferase (ALT) values throughout. Twenty-two percent of patients complained of symptoms, with hepatitis C being the cause in 82% of these. Two patients lost their HCV-RNA for prolonged, ongoing periods of time. The severity of the posttransplantation hepatitis was unrelated to age, sex, severity of liver disease before transplantation, cold ischemic time of the graft, duration of the operation, transfusions, the number of rejection episodes, or the long-term immunosuppressive regime. Only initial short-term therapy with interleukin 2 (IL2) receptor antibodies adversely influenced inflammatory activity. Viral genotype did not influence the course of the graft hepatitis in our series. Histology showed inflammation in 88% of the biopsies and signs of fibrosis in 24%. Mean ALT values correlated with inflammation but not with fibrosis in the biopsies. Porto-portal bridging was observed in six patients, one patient developed cirrhosis within 2 years after orthotopic liver transplantation (OLT). We conclude that chronic hepatitis develops in the majority of patients with HCV infection after liver transplantation. Carrier states without significant laboratory abnormalities are observed in approximately 16%, biochemical abnormalities without symptoms are seen in 60%, and symptomatic disease develops in a quarter of the patients. The disease course closely resembles that seen in nontransplanted hepatitis C patients. It is generally mild but little over 10% of patients develop signs of fibrosis of the graft during the first decade.