The aim of this open trial was to assess the efficacy and the safety of interferon (IFN) alfa therapy in liver transplant recipients with chronic active hepatitis caused by hepatitis C virus. In July 1991, among 447 liver recipients regularly observed at our institution, 46 had developed HCV-related chronic active hepatitis defined by piece meal necrosis. Fourteen of these 46 patients received IFN alfa 3 mIU three times weekly for a planned duration of 6 months and were compared to the 32 untreated patients. Genotyping and quantification of viremia were performed using type-specific amplification and branched DNA assay. Histological follow-up was available in all patients and routinely before and after IFN therapy. Treated and untreated patients did not differ regarding gender, age, length of follow-up, maximum histological score, and genotypes (41 of 46 were of type 1b). Induction of chronic rejection was observed in 5 of 14 treated patients leading to retransplantation in 3. In contrast, chronic rejection occurred in 1 of 32 untreated patients (P < .005) during the posttransplantation follow-up. Among the 9 treated patients without rejection, a decrease of transaminases or of HCV RNA levels of more than 50% were observed in 8 and 4, respectively; 2 patients had a complete response, and 1 did not relapse after discontinuation of IFN. Histological improvement occurred in 2 of the treated patients and in none of the untreated patients. IFN therapy in liver transplant recipients has poor antiviral effect and can induce chronic rejection. Its use in this setting should be cautious.