Recurrent hepatitis C virus (HCV) in liver transplant patients is a major cause of graft loss, liver failure, and need for retransplantation. The results available to date with the use of interferon alfa (IFN-alpha) in the treatment of recurrent HCV in liver transplant patients have been disappointing. The aim of this study was to evaluate the efficacy and clinical utility of post-transplant combination therapy with IFNalpha2b (3 million units 3 times weekly) and oral ribavirin (1,200 mg/d) for a duration of 6 months, followed by maintenance with ribavirin alone for an additional 6 months. Twenty-one liver transplant recipients with recurrent hepatitis C infection (HCV-RNA-positive; active hepatitis without rejection on biopsy) were enrolled in this study. Pretreatment serum alanine transaminase (ALT) levels were at least two times the upper limit of normal. Before treatment, all patients were HCV-RNA-positive and mean HCV-RNA titers were 125 million genome-equivalents/mL. Mean pretreatment histological score was 6.3 +/- 2. After 6 months of combination therapy, all 21 patients had normal ALTs. Ten patients (48%) cleared HCV-RNA from their serum, as assessed by polymerase chain reaction (PCR), and HCV-RNA levels decreased significantly in the others (P = .0001). Improvement in histological score was seen in all patients after combination therapy (P = .0013). During maintenance ribavirin monotherapy, ALT remained normal in all but 1 of the 18 patients who tolerated therapy. HCV-RNA reappeared in 5 patients, but HCV-RNA levels did not return to pretreatment levels (P = .0004). Comparison of pretreatment and postribavirin monotherapy liver biopsies revealed improvement in all but 1 of the 18 patients who tolerated ribavirin (P = .0002). Side effects were restricted to anemia, which necessitated cessation of ribavirin therapy in 3 patients. No patient experienced graft rejection during the study period. These results are significantly better than those reported with IFN-alpha monotherapy. Most importantly, there was a complete absence of graft rejection. These results suggest that the combination of IFN-alpha and ribavirin is effective in reducing HCV-RNA levels and ameliorating hepatocellular injury in recurrent HCV after liver transplantation, and that maintenance therapy with ribavirin monotherapy can maintain the biochemical and histological response.