We have studied HLA antigen profiles of the Inupiaq and Yupik-speaking peoples, two of the four Eskimo linguistic groups residing in Alaska. A relatively restricted polymorphism of HLA-A and -B locus antigens was noted. Only 35% of A locus specificities and 37% of B locus specificities tested for were detected in each population. The most common A locus alleles were A2, A24, and A28; the most common B locus alleles were B51(5), B27, B35, Bw60(40), Bw61(40), and Bw62(15). The antigens Cw3 (75 and 69%) and DR4 (81 and 67%) were found in high frequency in both groups. HLA-DR1, DR2, and DR7 were detected infrequently, while DR3 was not detected at all. DR4 was frequently associated in both Inupiats and Yupiks with Dw4, a specificity that was thought to occur only in Caucasian populations. A statistically significant difference between Inupiats and Yupiks was found for polymorphism at the A locus, but no significant differences were found for polymorphisms at the B, C, D, or DR loci. Analysis of HLA linkage disequilibrium revealed the presence of several novel haplotypes not previously described in other populations, suggesting that the selective factors responsible for positive associations observed in these Native Alaskans were probably distinct.