We examined synovial membrane samples from 6 rheumatoid arthritis (RA) and 3 osteoarthritis patients and from 1 normal subject, by an immunoelectron microscopic technique using anti-HLA-DR (anti-Ia) and anti-monocyte/macrophage (63D3) monoclonal antibodies. In the lining layer, the type A macrophage-like cells were strongly DR+ and 63D3+, whereas the type B fibroblast-like cells were almost completely negative. Lymphocyte-rich areas (containing more than 90% densely packed lymphocytes) showed weak and patchy DR staining of the lymphocytes. In these areas, 3-5% of the cells were macrophage-like cells which were 63D3-, a type of staining compatible with that of the interdigitating cell (IDC). In the plasma cell-containing (transitional) areas, many strongly DR+ macrophage-like cells were observed in close contact with lymphocytes and plasma cells. Ten to twenty percent of these cells were 63D3-, which suggests that they were IDC. Cells with the structural appearance of IDC were most frequently seen in those transitional areas which contained elevated concentrations (50-70%) of lymphocytes. In uninfiltrated interstitial areas, approximately 50% of the cells stained strongly with both anti-DR and 63D3 antibody, indicating that they were cells of monocyte/macrophage lineage, presumably histiocytes. This investigation has demonstrated the presence of the DR antigen in the RA synovial membrane on 1) phagocytic cells of the lining area, 2) lymphocytes and small numbers of IDC-like cells in dense, lymphocyte-rich areas, 3) large numbers of macrophage-like cells, of which some had the morphologic appearance of IDC, in transitional or plasma cell-containing areas, and 4) histiocytic cells in uninfiltrated interstitial areas. The observation of large numbers of DR+ macrophages and IDC-like cells in close contact with lymphocytes and plasma cells in the RA synovial membrane emphasizes their role in an active immune response. The observation of substantial numbers of potentially immunocompetent, DR+ histiocytic cells in uninfiltrated regions of the synovial membrane suggests that such cells may play a role in the progression of the synovial inflammatory reaction.