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Chronic hepatitis B is a serious infectious liver disease that often progresses to liver cirrhosis and hepatocellular carcinoma; however, clinical outcomes after viral exposure vary enormously among individuals. Through a two-stage genome-wide association study using 786 Japanese chronic hepatitis B cases and 2,201 controls, we identified a significant association of chronic hepatitis B with 11 SNPs in a region including HLA-DPA1 and HLA-DPB1. We validated these associations by genotyping two SNPs from the region in three additional Japanese and Thai cohorts consisting of 1,300 cases and 2,100 controls (combined P = 6.34 × 10⁻³⁹ and 2.31 × 10⁻³⁸, OR = 0.57 and 0.56, respectively). Subsequent analyses revealed risk haplotypes (HLA-DPA1^*0202-DPB1^*0501 and HLA-DPA1^*0202-DPB1^*0301, OR = 1.45 and 2.31, respectively) and protective haplotypes (HLA-DPA1^*0103-DPB1^*0402 and HLA-DPA1 …