The reactivity of rabbit anti-HLA-DR antigen antibodies with cells in normal and rheumatoid synovial tissue was investigated by indirect immunofluorescence on frozen sections of tissue. The antibodies reacted with a significant proportion of the synovial lining cells of both normal and rheumatoid synovial tissue, with endothelial cells, and with a number of, most probably, migratory cells. After dispersion of cells from rheumatoid synovial tissue by digestion with collagenase and DNase, adherent cells of both a macrophage-like and a dendritic appearance reacted with the anti-HLA-DR antigen antibodies. The adherent cells were also found to be potent stimulators in the allogeneic MLR. In addition, it was found that a high percentage of T lymphocytes from both peripheral blood and synovial tissue of rheumatoid patients bound anti-HLA-DR antibodies. The present data suggest a role for synovial lining cells in HLA-D-locus-dependent events of importance in the pathogenesis of rheumatoid arthritis and other joint diseases and point to the need for further investigations on T lymphocytes derived from the site of inflammation in the study of rheumatoid arthritis.