Although interferon alfa (IFN-alpha) and ribavirin are widely used in the treatment of hepatitis C, their role in the transplant recipient is unclear. We conducted a pilot study to determine the efficacy and safety of this therapy in transplant recipients with recurrent hepatitis C. Patients at least 6 months posttransplantation were treated with IFN-alpha 3 million units 3 times a week subcutaneously and ribavirin 800 mg daily by mouth for 48 weeks followed by ribavirin monotherapy for 24 weeks. The primary end point was sustained virologic response, and secondary end points included biochemical, virologic, and histologic responses at the end of combination treatment. Thirty-eight patients initiated therapy but 16 withdrew due to adverse effects, including 2 with myocardial infarction. Median age was 50 years; 74% were men, and 91% had genotype 1. The median interval between transplantation and enrollment was 23 months. On an intention-to-treat basis, 7 patients (18%) had a biochemical and 5 (13%) had a virologic response at the end of combination treatment. Inflammatory activity did not change, but fibrosis worsened in virologic nonresponders. Ribavirin maintenance caused a further decrease in serum alanine aminotransferase levels, but hepatitis C virus (HCV) RNA levels increased. Only 2 of the 38 patients (5%) had a sustained virologic response. Several patients required treatment with erythropoietin for anemia. In conclusion, IFN-alpha and ribavirin are effective in a small proportion of liver allograft recipients with recurrent hepatitis C. Adverse effects occur commonly, requiring dose reductions and treatment withdrawal.