HLA-DR, HLA-DQ, and T cell receptor beta (TCR beta) chain gene polymorphisms were investigated in 43 patients with rheumatoid arthritis (RA), in 10 patients with Felty's syndrome (FS), and in 5 RA multicase families. RA was found to be strongly associated with a DRB1 gene sequence motif present in DR1, DR4-Dw4, and DR4-Dw14 alleles. Ninety-three percent of RA patients were positive for at least 1 of these alleles, providing strong support for the "shared epitope hypothesis." The frequency distribution of this sequence motif suggests a dominant mode of inheritance. All 10 FS patients were DR4-Dw4 positive. Different DR-DQ associations among DR4 positive RA and FS patients indicate heterogeneity in the genetic susceptibility to these 2 disease entities. Furthermore, analyses of TCR V beta 8, V beta 11, and C beta gene polymorphisms did not support the notion of an influence of TCR beta germline allotypes on RA susceptibility.