The occurrence of disease and the inheritance of histocompatibility leukocyte antigens (HLA) were evaluated in 11 patients with the polyglandular failure syndrome and 42 of their relatives. The gene frequency of the HLA-B8 allele (seven of 22) and the HLA-A1, B8 haplotype phenotype frequency (five of 11) were increased in patients with polyglandular failure as compared with a control population. Eleven of 42 relatives had a polyglandular failure illness. Disease prevalence correlated with HLA inheritance in some families, but not all. Patients and diseased relatives had a high incidenceof immunologic dysfunction: autoantibodies, including antinuclear antibodies; elevated serum immunoglobulins (three of 16); abnormal skin tests (four of nine). Polyglandular failure appears to be an HLA-B8-associated syndrome with a high prevalence of disease in relatives. Immunologic dysfunction resulting from a gene(s) on chromosome 6, in linkage dysequilibrium with the HLA-B8 allele, may be a factor in the pathogenesis of polyglandular failure illnesses.