In a new series of RA patients the association with HLA-DR4 was again found to be highly significant. Also increased were the DR4 associated antigens DRw53 and DQw3. Hybridization of a DQ-beta probe to Bg1 II-digested DNA showed that a variant of DQw3, characterized by a 4.3 kb fragment and related to the serological specificity TA10, was markedly increased among DR4 positive RA patients. HLA-DR1 was also increased in RA and appeared to be independent of the increase of DR4. Although the DR1 association was weaker, it was observed in both patients with and without RF. In contrast, DR4 was found to be increased significantly only in the RF positive group of patients, as previously observed. Development of RA in multiple-case families was found to be linked to the inheritance of DR4 positive haplotypes. The possible role of risk factors associated with polymorphic markers of the T-cell receptor genes was investigated. An allelic marker associated with one of the variable gene subfamilies of the beta-chain was found to be associated with RA. The results suggest that susceptibility for development of RA is influenced by alleles of the T-cell receptor in conjunction with the class II HLA factors with which the T-cell receptor interacts in the course of the immune response.