To determine whether the hepatitis C virus (HCV) E2 PePHD sequence (aa 659-670; PKR-eIF2alpha phosphorylation homology domain) is the determinant for the response of interferon treatment, we have analyzed PePHD sequences in HCV-infected patients who had received interferon-alfa treatment. The PePHD sequence from all (6/6) of the patients, who are non- or partial responders to the interferon treatment, is the wild-type sequence (RSELSPLLL-TT, consensus sequence of HCV-1a and HCV-1b). However, there are sequence variations from more than half (5/9) of the patients, who are complete responders to the treatment. We have also analyzed the NS5A ISDR sequence (aa 2209-2248, interferon sensitivity-determining region) variation in HCV-1b-infected patients. No such correlation has been observed. Thus, our data suggest that HCV E2 should play a more important role than NS5A in determining the interferon responses.