Because Alaskan Eskimos have the greatest known endemic risk of Haemophilus influenzae type b (Hib) disease and represent a comparatively homogeneous population, we selected this population to evaluate the presence or absence of an association of 35 genetic markers (alleles or allotypes) at 12 chromosomal loci with susceptibility to both invasive Hib disease risk and level of Hib anticapsular antibody. We studied nearly all Alaskan Eskimo children who had had invasive Hib disease between 1971 and 1982 in southwestern Alaska (n = 103) and an equivalent number of controls matched for age, race, and village of residence, and verified not to have had proved or suspected Hib disease. We found no significant associations with Hib disease for the single alleles of HLA-A, -B, -C, -DR, Gm, Km, Am, Kidd, MNSs, ABO, esterase D, or glutamate pyruvate transaminase loci. However, we observed a significant interaction of two loci, Gm(a;..;g,s,t) allotype and HLA-DR8 (P = 0.002), with increased Hib disease susceptibility, and an interaction of the same Gm allotype and HLA-DR5 with decreased disease susceptibility (P = 0.01). We also compared the level of anticapsular antibody to Hib with each genetic marker and two-locus interactions, but no genetic association with antibody level was found. We conclude that some genetic factors contribute to the susceptibility to invasive Hib disease in this population.