Chronic hepatitis C is a common cause of viral liver disease in kidney transplant (KT) recipients. To assess the efficacy and safety of therapy with interferon alpha we conducted a prospective study where 14 cadaveric KT recipients with chronic hepatitis C received recombinant interferon alpha-2b (IFNa) 3 million units three times weekly (scheduled) for 6 months (group A). 14 KT recipients with chronic hepatitis C were not treated and served as controls for the study period (group B). All the patients in both groups had had stable renal function for at least one year. All patients in both groups had a positive HCV viremia at the beginning of the study. Patients of group A were treated for 142±34.8 days (range 65–168); elevated serum aminotransferase (ALT) levels decreased rapidly and significantly from 100.3±48.9 to 37.7±13.9 IU/L (P=0.001); 10 patients (77%) were “responders,” whereas the others experienced a decrease in ALT values but without reaching the normal ranges. With a mean follow-up of twelve months after discontinuation of IFNa therapy, 8 responders—i.e., 80%—relapsed within 1–20 weeks. Only 4 patients had no detectable HCV viremia at the end of the IFNa; two of them already have abnormal values of ALT. Moreover HCV viremia was present in all patients one month after the cessation of IFNa treatment. Side effects of IFNa (fatigue, anorexia, weight loss) were frequent, and 3 patients decided to drop out of the treatment. The hematological tolerance was good although there was a significant decrease in hemoglobin (11.9±1.7 vs. 13.4±1.7 g/dl; P=0.0044). In group B, serum ALT levels did not significantly decrease (84.2±47.6 vs. 105.2±68.8 IU/L). At the end of the study period serum ALT levels were significantly lower in group A than in group B (37.7±13.9 vs. 84.2±47.6 IU/L, P=0.013). The major concern in group A was the occurrence of 5 renal failures. Kidney transplant biopsies showed edema, no significant tubulitis, scarcely scattered interstitial inflammatory cellular infiltration, and mesangial thickening. Four patients received methylprednisolone pulses but renal function improved in only two cases. We were not able to discover predictive factors of renal failure. We conclude that IFNa therapy is effective in controlling disease activity—i.e., reducing aminotransferase levels in KT patients with chronic hepatitis C, although relapse and detection of HCV RNA after the cessation of treatment were observed, respectively, in 80% and 100% of patients. Finally the high rate of renal function impairment is unacceptable. Thus IFNa is not a suitable treatment for these patients.