Clinical and epidemiologic observations, including the association of Graves' disease (GD) and Hashimoto's thyroiditis (HT) with the HLA gene complex, support a role for specific disease-related genes in the development of autoimmune thyroid disease (AITD). The combination of HLA and immunoglobulin heavy chain allotypes (Gm) has previously been reported to be predictive of AITD in multiply affected Japanese families. We have investigated the immunogenetics of AITD in families in the United States. Twenty-seven pedigrees including 15 with GD, 8 with HT, and 4 with both HT and GD were immunogenetically typed and analyzed for population and within family disease associations. The majority of families (63%) were multiplex for AITD. HLA-DR3 was increased in affected family members with GD and HLA-DR5 was increased in affected family members with HT. Formal linkage analysis was applied to test for coinheritance of disease with the HLA locus within families. The LIPED computer program was used to calculate the probability of linkage in terms of the lod score. Evidence from linkage analysis was consistently against linkage of either GD or HT to the HLA region under various penetrances and different modes of inheritance. The combination of HLA and Gm was not found to be predictive of disease in 7 selected multiplex families with multigenerational instances of AITD. T cell function was also examined in 3 pairs of siblings genetically identical for HLA and Gm but discordant for disease expression. We found no evidence of a global T cell defect in the small number of patients examined. We conclude that whereas there is an association of AITD with the HLA region, our linkage analysis demonstrates that alleles of the HLA region are not cosegregating with either GD or HT within these families. Thus, whereas HLA may increase susceptibility to AITD, as shown by the existence of an HLA association, the major genetic influence on the inheritance of AITD must be at another locus.