A genetic component to nasopharyngeal carcinoma (NPC) has been suggested by associations of the malignancy with human leukocyte antigens (HLAs) in Southern Chinese populations, among which NPC is a major cancer. Data from other races are inconclusive. We have investigated associations between NPC and HLA antigens at the HLA-A, B, C, and DQ loci and alleles at the DRB1 locus in a population-based, multicenter investigation in the United States. Data from 82 cases and 140 controls are presented, making this the largest study population analyzing data from Caucasians to date. HLA frequencies from study cases were also compared with external control groups from the 11th International Histocompatibility Workshop and the National Marrow Donor Program. Logistic regression methods were used to investigate the effects of the joint occurrence of multiple HLA types and to assay for differences in HLA-associated risk in different age groups. A meta-analysis was undertaken to compare and summarize our results with previously published findings. The meta-analysis found a protective association with A2 antigen in non-Chinese [odds ratio (OR), 0.63; P < 0.001], a protective association with A11 across all races (OR, 0.54; P < 0.001), and an increased risk associated with B5 in Caucasians (OR, 2.81; P < 0.001). The present study also found independent associations, in a logistic regression model, between NPC and DRB1*1501 (OR, 0.33), DRB1*0405 (OR, 7.57), and Cw3 (OR, 0.42), although these data must be interpreted cautiously due to multiple-testing considerations. Associations were found to be more pronounced in younger patients for A2, A11, A28, B8, and B51.