Nasopharyngeal carcinoma (NPC), which occurs at a disproportionately high rate among Chinese individuals, is associated with Epstein-Barr virus (EBV). Human leukocyte antigen (HLA) polymorphisms appear to play a role in NPC, because they are essential in the immune response to viruses. We used high-resolution HLA genotyping in a case-control study in Taiwan to systematically evaluate the association between various HLA alleles and NPC.We matched 366 NPC case patients to 318 control subjects by age, sex, and geographic residence. Participants were interviewed and provided blood samples for genotyping. High-resolution (polymerase chain reaction-based) genotyping of HLA class I (A and B) and II (DRB1, DQA1, DQB1, and DPB1) genes was performed in two phases. In phase I, 210 case patients and 183 control subjects were completely genotyped. In phase II, alleles associated with NPC in the phase I analysis were evaluated in another 156 case patients and 135 control subjects. Extended haplotypes were inferred.We found a consistent association between HLA-A*0207 (common among Chinese but not among Caucasians) and NPC (odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.5 to 3.5) but not between HLA-A*0201 (most common HLA-A2 allele in Caucasians) and NPC (OR = 0.79, 95% CI = 0.55 to 1.2). Individuals with HLA-B*4601, which is in linkage disequilibrium with HLA-A*0207, had an increased risk for NPC (OR = 1.8, 95% CI = 1.2 to 2.5) as did individuals with HLA-A*0207 and HLA-B*4601 (OR = 2.8, 95% CI = 1.7 to 4.4). Individuals homozygous for HLA-A*1101 had decreased risks for NPC (OR = 0.24, 95% CI = 0.13 to 0.46). The extended haplotype HLA-A*3303-B*5801/2-DRB1*0301-DQB1*0201/2-DPB1*0401, specific to this ethnic group, was associated with a statistically significantly increased risk for NPC (OR = 2.6, 95% CI = 1.1 to 6.4).The restriction of the association of HLA-A2 with NPC to HLA-A*0207 probably explains previously observed associations of HLA-A2 with NPC among Chinese but not Caucasians. The extended haplotypes associated with NPC might, in part, explain the higher rates of NPC in this ethnic group.