Chronic hepatitis B virus (HBV) infection is a major health issue, especially in Asia. A recent genome-wide association study (GWAS) implicated genetic variants in the human leukocyte antigen (HLA)-DP locus associated with chronic hepatitis B in Japanese and Thai populations. To confirm whether the polymorphisms at the HLA-DP genes are associated with persistent chronic HBV infection in Han Chinese, we conducted an independent case-control study using 521 persistent chronic HBV carriers and 819 controls that included 571 persons with HBV natural clearance and 248 never HBV-infected (healthy) individuals. Eleven single nucleotide polymorphisms (SNPs) in a region including HLA-DPA and HLA-DPB and an adjacent SNP in strong linkage disequilibrium (LD) with a neighboring HLA-DR13 locus were genotyped using the TaqMan SNP genotyping assay. Eleven variants at HLA-DP showed a strong association with persistent chronic HBV carrier status (P = 1.82 × 10−12 to 0.01). We also stratified the analysis by HBV clearance status to test the association between these polymorphisms and HBV natural clearance; similar results were obtained (P = 2.70 × 10−11 to 0.003). Included SNPs define highly structured haplotypes that were also strongly associated with HBV chronic infection (block 1: odds ratio [OR] = 0.54, P = 8.73 × 10−7; block 2: OR = 1.98, P = 1.37 × 10−10). These results further confirm that genetic variants in the HLA-DP locus are strongly associated with persistent HBV infection in the Han Chinese population. (HEPATOLOGY 2011;53:422-428)