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Background: Suppression of the progression to cirrhosis and hepatocellular carcinoma is important, especially for young hepatitis C virus (HCV)-infected patients. The aim of this study was to analyze the response to interferon (IFN) monotherapy in young HCV patients., Methods: Between 1989 and 2002, 1021 anti-HCV-positive patients hospitalized at Toranomon Hospital received IFN monotherapy. Among these patients, 144 were < or =35 years of age, while the remaining 877 were 36-73 years old. We retrospectively identified 209 patients with known dates of blood transfusion (i.e., start of HCV infection) among the 1021 patients. IFN treatment lasted 6 months., Results: HCV RNA level (P < 0.001), HCV genotype (P < 0.001), age (P < 0.001), and liver histology (P = 0.01) were identified as determinants of the response to IFN monotherapy in 1021 patients. Moreover, in patients with high viral load and genotype 1b, the sustained virological response (SVR) rate was significantly higher in those aged < or =35 years than in older patients (P < 0.001). In patients with genotype 1b with known date of blood transfusion, a longer duration of infection negatively influenced the SVR rate. In the 209 patients, multivariate analysis identified HCV RNA level (P < 0.001), age (P = 0.002), and duration of infection (P = 0.049) as determinants of SVR., Conclusions: The response of IFN monotherapy is better in patients aged < or =35 years than in older patients, probably because of mild stage histology, the effect of host-related factors, and shorter period of infection. Long-term IFN monotherapy may be suitable for young women who desire to become pregnant or those with anemia.