Although T cells from patients with rheumatoid arthritis (RA) have previously been determined to have poor proliferative responses to a variety of stimuli, the underlying mechanism is not known. We have investigated the expression of the signal-transducing zeta molecule in subsets of T cells and natural killer (NK) cells derived from the peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) of RA patients using quantitative flow cytometry, Western blot analysis and immunohistochemistry. A decrease of zeta expression was apparent in all investigated lymphocyte subsets from the PBMC and SFMC of RA patients, as compared to the corresponding subsets from healthy age- and sex-matched controls. A less pronounced reduction of cell surface-located CD3 epsilon, CD4 and CD8 was also located in T cells from SFMC as compared to PBMC from RA patients. Biochemical demonstration of the low or absent CD3 zeta in PBMC from patients with RA was achieved by Western blot analysis. Immunohistochemical staining and image analysis also confirmed the low expression of zeta chains in synovial tissue of RA patients. The possibility that the decreased expression of zeta and of immune functions of T cells from RA patients may be related to the presence of free oxygen radicals, as we have previously reported in cancer patients, should be considered.