This study investigated clinical implications of human leukocyte antigen (HLA) I and II haplotypes, in combination with HBV sub-genotype C2, in hepatitis B virus (HBV) infections in northeastern China. Here, HLA haplotypes of 230 HBV-infected patients were compared to 210 healthy, unrelated Han individuals. Of the 230 HBV-infected patients, 54 had acute self-limited hepatitis (ASH) with sub-genotype C2 (ASH-C2), 144 had chronic hepatitis (CH) with sub-genotypes C2 and B2 (CH-C2 and CH-B2), and 32 spontaneously recovered without sub-genotype results. All groups underwent HLA typing and haplotype analysis. The results revealed that A*02-DRB1*12 and A*02-B*15-DRB1*09 carriers were susceptible to HBV infection. A*02-B*15-DRB1*09 is probably associated with acute onset and viral clearance and A*02-DRB1*12, with viral persistence. In HBV infections, B*40-DRB1*12 was associated with HBV persistence, whereas B*46-DRB1*09, A*24-DRB1*14, and B*15-DRB1*04 carriers easily recovered from the disease. By contrast, when infected with the HBV-C2 sub-genotype, A*24-DRB1*14, B*15-DRB1*04, A*02-B*15, A*02-DRB1*15, and A*02-B*15-DRB1*09 carriers displayed an acute clinical course before recovery. This study reveals a relationship between HLA haplotypes and HBV pathogenesis, thereby providing potential therapeutic targets to treat HBV infection.