Rheumatoid arthritis is genetically linked to major histocompatibility complex (MHC) molecules (HLA-DR4 and related molecules) and characterized pathologically by high levels of HLA-DR expression and infiltration of proliferative of synovial tissue with CD4+ T lymphocytes. T-lymphocyte activation is driven by specific signaling through polymorphic alpha/beta T-cell receptors (TCRs) that are reactive with antigen-MHC complexes present at the sites of inflammation. We are interested in characterizing rheumatoid TCRs molecularly to ascertain potential binding surfaces for antigen+MHC in synovial tissue. Accordingly, we have recently investigated the TCR alpha and beta chain heterogeneity in a series of 10 rheumatoid synovia obtained at the time of joint surgery. The most frequently detected V beta families were V beta 12, 14, and 17, each of which was found in 80% of specimens. We report here the molecular cloning and sequence analysis of 20 cloned V beta segments amplified with a V beta 14 family-specific TCR primer, and six cloned V beta segments amplified with a V beta 17 family-specific TCR primer from four rheumatoid synovia. Comparison with the data base revealed that these sequences belonged to the closely related V beta 3, V beta 14, and V beta 17 families. Dominant clones were apparent in two of the individuals by the presence of identical V-D-J regions, suggesting an antigen-driven process. Amino acid sequence analysis revealed a conserved motif in the putative fourth hypervariable region or CDR4. Molecular modeling of this epitope suggests that charged side chains are available for binding to ligand structures (e.g., antigen, MHC, or superantigen). We suggest this epitope may play a role in the molecular pathogenesis of rheumatoid arthritis.