Analyzing data from Caucasians participating in a multicentered population-based case-control study of nasopharyngeal carcinoma and HLA type in the US, we found persons with the A2 antigen to have a significantly lower risk than those with other antigens at the A locus [odds ratio (OR), 0.46; 95% confidence interval (CI), 0.21-0.96]. The protective association was stronger among presumptive homozygotes for A2. Similar results were obtained when cases were compared with US Caucasians typed either as part of the Collaborative Transplant Study, or by the 9th International Histocompatibility Workshop. These results are supported by a statistical summary of odds ratios for A2 from a number of previous studies in non-Chinese (summary OR, 0.69; 95% CI, 0.54-0.88). The odds ratio for patients with squamous-cell carcinomas was 0.56; among 7 patients with undifferentiated tumors the OR was 0.14. Results from in vitro studies of immune response to Epstein-Barr virus have found that the HLA-A2 antigen efficiently presents the EBV gene product LMP-2, which has been detected in NPC tumor cells. This offers a rationale for the observed protective association between the HLA-A2 antigen and nasopharyngeal carcinoma.