Nasopharyngeal carcinoma (NPC) has been known to be associated with specific HLA haplotypes, in particular HLA A2, B46 and A33, B58 haplotypes. A linkage study based on this observation suggested that HLA antigens are not the cause of NPC but that there exists a gene that lies close to if not within the major histocompatibility complex locus and confers a greatly increased relative risk of NPC. Since then, no further work has elucidated the presence of this gene. One of the difficulties faced by researchers has been the size of the region of chromosome implicated. The MHC locus alone is almost 4 Mb in length, and the number of genes encoded within it is numerous. The purpose of our study was thus to reduce the region of DNA in which the NPC susceptibility gene is likely to be. We report that the NPC susceptibility gene may be within the centromeric end of the class-1 and the telomeric end of the class-III regions of the MHC, near the D6S1624 microsatellite locus, where the presence of allele 4 of the microsatellite conferred a 3 1/2-fold increase in the risk of NPC, the highest reported for a single locus, and the presence of allele 1 of the same microsatellite conferred a highly significant protective effect against NPC.