HLA associations with Sjögren's syndrome (SS), previously defined by serologic HLA typing, are reviewed. Because the SS-A/Ro and SS-B/La autoantibody responses in SS and systemic lupus erythematosus (SLE) show even stronger correlations with HLA alleles, HLA-DR and DQ alleles were examined using restriction fragment length polymorphisms (RFLP) in white and black patients with SS and/or SS having anti-Ro and anti-La antibodies. The strongest associations across ethnic lines were with HLA-DR3, DQw2 and DQw1.2 (DQw6), especially the DQw1.2 (DQw6)/Dqw2 heterozygous state. HLA-DQw3 was relatively decreased. These data suggest that HLA-DQ is most likely responsible for these abnormal autoantibody responses. In addition, multiplex family studies of Ro antibodies demonstrates the requirement for both HLA and non-MHC effects.