Abstract Background Pegylated (PEG)-interferon (IFN)-alfa-2a plus ribavirin (RBV) therapy for 24 weeks is now a standard treatment protocol for patients with hepatitis C virus (HCV) genotype 2. As RBV cannot be used in certain situations, we examined whether PEG-IFN-alfa-2a monotherapy for 24 weeks or less would be sufficient to obtain a sustained virological response (SVR) in patients infected with HCV genotype 2. Methods Forty-nine consecutive patients with HCV genotype 2 received PEG-IFN-alfa-2a (180 μg/week) subcutaneously without oral RBV for 8-64 weeks. HCV RNA level was determined by COBAS AMPLICOR HCV Test, v2.0. Results HCV RNA was equal to or less than 100 KIU/mL (defined as low viral load) in 15 of 49 patients, and the remaining 34 had HCV RNA above 100 KIU/mL (defined as high viral load). All 15 patients with low viral load achieved rapid virological response (RVR; HCV RNA negative at week 4), and also achieved SVR with an average treatment duration of 17.1 weeks. The 34 patients with high viral load were treated for 33.7 weeks on average, and 19 of them (55.9%) achieved RVR. The SVR rates of these patients were significantly higher in those with RVR than without RVR (16/19 vs. 6/15 p = 0.0074). Conclusion PEG-IFN-alfa-2a monotherapy for 24 weeks or less might be sufficient to treat selected patients with HCV genotype 2, especially those with low viral load and becoming negative for HCV RNA by week 4 of treatment.