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-alpha) 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-alpha (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 Twenty-eight patients completed the treatment regimen, two ribavirin-treated patients being withdrawn because of severe hemolysis.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-alpha (43%; P=.01). Lobular inflammation was reduced in 9/14 ribavirin-treated (64%) and 3 of 14 IFN-alpha-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-alpha-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-alpha 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.