Objective. The long-term effects of multi-course interferon (IFN) monotherapy in patients infected with hepatitis C virus (HCV) are still unclear. Material and methods. To evaluate the effects of multi-course IFN on hepatocarcinogenesis and survival, a follow-up study was conducted comprising 454 consecutively recruited non-cirrhotic naive patients infected with HCV, who had received IFN monotherapy between 1987 and 1992. The median follow-up was 11.3 years. Results. A sustained response (SR) after the first IFN was achieved by 152 patients (33.5%) (Group A). Of 302 patients (66.5%) with non-SR after the first IFN, 130 patients (28.6%) did not receive additional IFN (Group B), and the remaining 172 patients (37.9%) received multi-course IFN monotherapy (Group C). With regard to hepatocarcinogenesis and survival rates for liverrelated deaths, Groups A and C both showed significantly better long-term clinical outcome than Group B (p < 0.001; log-rank test). Three independent factors were identified by multivariate analyses (fibrosis stage 3, Group B, and age ≥50) for all patients and two factors (fibrosis stage 3 and age ≥50) for Group C associated with hepatocarcinogenesis. With regard to hepatocarcinogenesis rates according to the mean alanine aminotransferase (ALAT) levels during the IFN-free period in Group C, significantly higher rates were noted in patients with ALAT levels above 1.5 ×the upper normal limit (17.6%)-than those below the limit (0%) (p < 0.05). Conclusions. Multi-course IFN monotherapy reduces the risk of hepatocarcinogenesis and increases survival, and low ALAT levels during the IFN-free period are associated with lower hepatocarcinogenesis rates in multi-course IFN. Objectives. The long-term effects of multi-course interferon (IFN) monotherapy in patients infected with hepatitis C virus (HCV) are still unclear. To evaluate the effects of multi-course IFN on hepatocarcinogenesis and survival, a follow -up study was designed containing 454 consecutively recruited non-cirrhotic naive patients infected with HCV, who had received IFN monotherapy between 1987 and 1992. The median follow-up was 11.3 years. Results. A sustained response (SR) after the first IFN was Of 302 patients (66.5%) with non-SR after the first IFN, 130 patients (28.6%) did not receive additional IFN (Group B), and the remaining 172 patients (37.9%) received regard to hepatocarcinogenesis and survival rates for liver associated deaths, Groups A and C both significantly better long-term clinical outcome than Group B (p <0.001; log-rank test). Three independent factors were identified by multivariate analyzes (fibrosis stage 3, Group B, and age ≥50) for all patients and two factors (fibrosis stage 3 and age ≥50) for Group C associated with hepatocarcinogenesis. With regard to hepatocarcinogenesis rates according to the mean alanine aminotransferase (ALAT) levels during the IFN-free period in Group C, significantly higher rates were noted in patients with ALAT levels above 1.5 × the upper normal limit (17.6%) - than those below the the limit (0%) (p <0.05) Conclusions. Multi-course IFN monotherapy reduces the risk of hepatocarcinogenesis and increases survival, and low ALAT levels during the IFN-free period are associated with lower hepatocarcinogenesis rates in multi-course IFN.