Hepatitis C virus (HCV) infection usually recurs after orthotopic liver transplantation (OLT), and most patients develop graft damage. This study compared the efficacy of interferon alfa (IFN-α) and ribavirin monotherapies in liver transplant recipients with chronic hepatitis C in the graft. Thirty OLT recipients with chronic hepatitis C were randomized to receive either IFN-α (3 MU three times a week) or ribavirin (up to 1.2 g daily) for 24 weeks. Virological, biochemical, and histological responses to treatment were assessed. Twenty-eight patients completed the treatment regimen, two ribavirin-treated patients being withdrawn because of severe hemolysis. Normalization of serum aspartate aminotransferase was achieved in 13 of 14 patients receiving ribavirin (93%) and 6 of 14 patients receiving IFN-α (43%; P = .01). Lobular inflammation was reduced in 9/14 ribavirin-treated (64%) and 3 of 14 IFN-α–treated patients (21%; P = .05), each of whom had a biochemical response. However, the total histological activity index did not improve in either the interferon (P = .43) or the ribavirin (P = .96) group. Posttreatment viremia levels were significantly reduced in IFN-α–treated (P = .05) but not in ribavirin-treated (P = .88) patients. Hemolysis occurred in all ribavirin-treated patients, with serum hemoglobin decreasing to <10 g/dL in 50%. Total leukocyte and lymphocyte counts decreased significantly during ribavirin treatment (P = .02 and P = .004, respectively). We concluded that in patients with chronic hepatitis C after OLT, IFN-α retains an antiviral effect whereas ribavirin is superior in achieving normalization of serum aspartate aminotransferase levels and reducing lobular inflammation, but not the total histological activity index. These findings provide a rationale for combination therapy in the post-OLT setting, although patients must be carefully monitored for hemolysis.