We have conducted a comprehensive case-control study of a nasopharyngeal carcinoma (NPC) population cohort from Guangxi Province of Southern China, a region with one of the highest NPC incidences on record. A total of 1407 individuals including NPC patients, healthy controls, and their adult children were examined for the human leukocyte antigen (HLA) association, which is so far the largest NPC cohort reported for such studies. Stratified analysis performed in this study clearly demonstrated that while NPC protection is associated with independent HLA alleles, most NPC susceptibility is strictly associated with HLA haplotypes. Our study also detected for the first time that A(*)0206, a unique A2 subtype to South and Southeast Asia is also associated with a high risk for NPC. HLA-A(*)0206, HLA-B(*)3802 alleles plus the A(*)0207-B(*)4601 and A(*)3303-B(*)5801 haplotypes conferred high risk for NPC showing a combined odds ratio (OR) of 2.6 (P<0.0001). HLA alleles that associate with low risk for NPC include HLA-A(*)1101, B(*)27, and B(*)55 with a combined OR of 0.42 (P<0.0001). The overall high frequency of NPC-susceptible HLA factors in the Guangxi population is likely to have contributed to the high-NPC incidence in this region.