HL-A typing of 144 NPC patients and 236 controls revealed an increased frequency of 1st locus HL-42 (relative risk = 2.24) and an increased frequency of unidentified antigens at the 2nd locus (relative risk = 2.60) in the NPC patients. HL-A2 and the 2nd locus "blank" appeared to act together (HL-A2 blank haplotype) in determining NPC risk in highest-risk Cantonese, whereas in relatively lower-risk non-Cantonese Chinese (Hokkiens, Teochews) they appeared to act independently. Only the "blank" had an increased frequency in Malay NPC patients. Thus there was an indication that the strength of the HL-A association with NPC reflected the 30-50-fold difference in incidence between highest-risk Cantonese and lowest-risk Indians. In Singapore, HL-A segregation patterns in families of nine Chinese NPC patients confirmed that the "blank" was a genetic phenomenon. A new 2nd locus antigen (Singapore-2) has recently been detected. Singapore-2 occurs more frequently in NPC patients and appears to be associated with a high risk for NPC. Since HL-A2 and Singapore-2 are not the risk factors, it is likely that the HL-A association with NPC reflects the existence of disease-susceptibility (DS) genes in linkage disequilibrium with alleles of the HL-A loci. It is proposed that NPC-DS genes may determine differences in immune responsiveness to environmental agents, and thereby determine differences in NPC incidence. If the known altered immune responsiveness of NPC patients to EBV reflects the function of DS genes linked to the high NPC risk HL-A type, then the hypothesis that Epstein-Barr virus has an etiological role in NPC can be tested by several types of prospective studies.