To understand the role of cytolytic lymphocytes in the pathogenesis of rheumatoid arthritis, we investigated the expression of lymphocyte cytotoxicity mediators, perforin, and serine esterases, in lymphocytes derived from the synovial fluid of 15 patients with rheumatoid arthritis. Previous work has shown that CD8+ lymphocytes that possess markers of activation appear to be present in rheumatoid arthritis (RA). By means of in situ hybridization techniques and immunohistochemical analysis, the authors show that perforin and two serine esterases (serine esterase 1/Hanukah factor/granzyme A, and serine esterase 2/granzyme B) are expressed by subpopulations of CD8+ and CD56+ lymphocytes obtained from synovial fluid. The presence of these cytotoxic mediators suggests a possible mechanism for tissue damage, and provides evidence implicating cytolytic lymphocytes in the pathogenesis of RA.