The relationships of human leukocyte antigen (HLA) and heavy chain immunoglobulin (Gm) haplotypes to disease and autoantibody expression were examined in six large kindreds, each having one or more members with primary Sjögren's syndrome. Various other autoimmune diseases and autoantibodies occurred among the 117 relatives in these families. The HLA and Gm haplotypes did not necessarily segregate persons into those with Sjögren's syndrome, other autoimmune disorders, or serologic abnormalities, but HLA alleles DR3 and DR2 occurred in significant excess in relatives with Sjögren's syndrome, irrespective of HLA haplotype. Segregation analysis suggested a Mendelian dominant genetic defect common to the many autoimmune diseases and serologic reactions that was not linked to HLA or Gm. A significant effect of female sex was also documented. These studies suggest that Sjögren's syndrome results from the interaction of several HLA-linked and non-HLA-linked genes.