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We recently reported that the interleukin (IL)-28B major genotype is a predictor of early suppression of the hepatitis C virus (HCV) at 12 weeks in response to pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy. The present study investigated the relationship between IL-28 genotypes and the virological response to PEG-IFN/RBV therapy at 24 and 48 weeks. Genotypes of the IL-28B rs8099917 T>G single nucleotide polymorphism were determined in 177 patients with HCV infection. Among them, 56 patients with HCV1 infection were treated with PEG-IFN/RBV. The frequency of the IL-28B major allele (TT) was 73.8% in patients with HCV serotype 1 and 86.3% in patients with HCV serotype 2. The rate of HCV-RNA positivity was significantly lower at 48 weeks in patients with the IL-28B major allele compared to patients with the IL-28B minor allele (TG or GG). The rate of HCV-RNA positivity at 24 weeks tended to be lower in patients with the IL-28B major allele, but there was no statistical significance (P=0.059). The sustained virological response (SVR) rate was 45.9% in patients with the IL-28B major allele, but 13.3% in patients with the IL-28B minor allele. The SVR correlated with the IL-28B major allele (OR=7.13, P=0.010), early virological response (OR=33.3, P=0.008), HCV-RNA ≤ 6.3 log IU/ml (OR=81.2, P=0.009) and γ-GTP ≤ 47 IU/l (OR=49.4, P=0.027). The IL-28B genotype is a significant pre-treatment predictor of the response to PEG-IFN/RBV therapy at 48 weeks in patients with HCV infection.