Genotyping of 179 consecutive Japanese chronic hepatitis C patients was carried out based on the variation in the hepatitis C virus (HCV) core gene. The results were correlated with clinical features and antibody responses toward specific HCV proteins deduced from the nucleotide sequence of genotype I/1a. Genotypes II/1b, III/2a, and IV/2b were identified in 138 (77%), 24 (13%), and 12 (7%) patients, respectively. Five patients had double infections. Genotype dependence was observed only for antibody response toward the NS4 (5-1-1) protein, which was infrequent in genotype III/2a patients (33%) compared with genotype II/1b (81%; P < 0.01) and genotype IV/2b (75%; P < 0.05). Following interferon-alpha therapy, sustained amniotransferase normalisation was achieved by 89% (eight of nine) patients without antibody to the 5-1-1 protein and 33% (17 of 51) with it (P < 0.01). These findings indicate that absence of antibody response to the 5-1-1 protein is frequent in genotype III/2a HCV carriers and may serve to predict responses to interferon therapy.