AbstractNPC is an epithelial tumor that is highly prevalent among the southern Chinese. Numerous studies have indicated that specific HLA haplotypes and genes within the HLA complex are associated with NPC. As a first effort to localize the gene responsible for susceptibility, the HLA‐A, ‐B, and ‐A2 subtypes were examined for their association to NPC. Consistent with previous reports, frequencies of HLA‐A2 [OR = 2.50, pc = 0.020 (study population); OR = 3.73, pc = 0.0030 (≥40 years old)] were significantly higher in patients with NPC than in healthy controls. Two‐locus analysis indicated that A2+B46+ individuals are at greater risk for NPC than A2−B46− individuals in both the population studied and the ≥40‐year‐old group. This, however, may be due to the close linkage of these 2 genes. Moreover, A2+B38+ individuals were at higher risk than A2−B38− individuals in both the population studied and the ≥40‐year‐old group; A2 and B38 are not genetically linked. These findings suggest that B38 or B46 alone cannot confer a high risk of NPC but that, in conjunction with A2, B38 or B46 positivity greatly increases risk. None of 5 A2 subtypes identified from studied populations was significantly associated with NPC. Microsatellite marker D6S211, located 97 kb telomeric to HLA‐A, was analyzed for its association with NPC. Allele 4 of D6S211 was significantly associated with NPC (OR = 3.97, pc = 0.0042). These results strongly support the hypothesis that genes associated with susceptibility to NPC in the HLA region are within the HLA‐A locus. © 2002 Wiley‐Liss, Inc.