Retransplantation for recurrent hepatitis C virus (HCV) has been evaluated in small series. In this study, patients undergoing transplantation for HCV-related cirrhosis with subsequent retransplantation more than 90 days for recurrent HCV (proven by pathologic examination of the explant and exclusion of other factors) were prospectively followed. This group was compared with a simultaneous cohort without HCV infection undergoing retransplantation more than 90 days after primary transplantation. Forty-two patients underwent retransplantation for recurrent HCV with a median survival of 12.9 +/- 6.7 months after retransplantation. Twenty patients (48%) were dead at 6 months, and 13 (65%) of these deaths were due to sepsis. On univariate analysis, creatinine level greater than or equal to 3 mg/dL, platelet count less than 100000/microL, prothrombin time (PT) greater than or equal to 16 seconds, alkaline phosphatase level less than or equal to 240 U/L, gamma-glutamyltransferase level less than or equal to 130 U/L, and donor age of 60 years or greater all correlated significantly with shorter survival after retransplantation. PT and donor age were predictors of survival on multivariate analysis. Patients undergoing retransplantation for recurrent HCV had a significantly shorter median survival than the 55 patients undergoing retransplantation for other chronic reasons of graft loss (75.6 +/- 17.7 months). In conclusion, median survival after liver retransplantation for recurrent HCV is significantly shorter than after retransplantation for other causes of late graft loss. Most deaths occur in the first 6 months and are due to sepsis. Candidates for retransplantation with a preoperative PT less than 16 seconds and those receiving grafts from donors younger than 60 years can expect a significantly longer median survival after retransplantation.