As part of the American Society for Histocompatibility and Immunogenetics coordinated studies among minority populations, human leukocyte antigen (HLA) alleles were defined for 460 volunteer Yup'ik Eskimos from the Yukon Kuskokwim delta region of southwestern Alaska. The study group included 252 adults with no other first-degree relatives and 48 informative nuclear families. Full Yupik ancestry through both maternal and paternal grandparents was claimed by 81.1% of participants. HLA-A, -B, -Cw, -DRB1, and -DQB1 alleles were determined by SBT, SSOP, reverse SSOP, and/or RSCA according to the protocols of five participating laboratories. Polymorphism was limited with 3-6 alleles comprising > 80% of the alleles observed at each locus. Homozygosity was high, particularly at the HLA-A and -DQB1 loci, with 36.6% and 44% of individuals having a single allele defined at these respective loci. HLA-A, -B, and -DRB1 alleles were in Hardy-Weinberg equilibrium, whereas HLA-Cw and -DQB1 alleles gave significant deviation (p = 0.002; 0.005). Significant linkage disequilibrium (p < or = 0.00001) was observed in all pairwise evaluations. A new Cw*0806 allele was observed in high linkage disequilibrium with B*4801(Delta = 0.099; Delta(rel) = 1.0). Three extended haplotypes were found to have frequencies > 5%, the most prevalent being A*2402; B*4801; DRB1*0401; DQB1*0301 (0.0933). Comparison of available class I data indicate that the Yup'ik share several common alleles with other Native American populations, including: A*2402, *0206, *6801; B*1501, *2705, *3501, *4002, *4801, *5101; and Cw*0202, *0304, *0401. Comparisons of class II data also confirm a close relationship of the Yup'ik to two other Eskimo populations, Siberian and East Greenland Eskimos. DRB1*0401 and *1101, which occur in high frequency among these Eskimo populations, but not in other Native Americans, were also prevalent among the Yup'ik, with respective frequencies of 0.232 and 0.107.