The activity of natural killer cells in the synovial fluid, the synovial tissue and the peripheral blood was studied in 23 patients with active rheumatoid arthritis and was found to be significantly lower than that in the blood of 28 controls. This decrease was inversely related to the erythrocyte sedimentation rate. The preincubation of mononuclear cells with indomethacin significantly increased the natural killer activity in the blood of the controls and the patients with rheumatoid arthritis, but did not have any effect in the synovial compartment. The elimination of the adherent cells increased the natural killer activity in the blood of the controls and the patients with rheumatoid arthritis, but decreased this activity in the synovium. The stimulatory effect of synovial macrophages and the suppressor effect of the blood macrophages on the natural killer activity were confirmed when the adherent and non-adherent populations were mixed and these effects were reproduced by using supernatants of total mononuclear cells. The stimulation of the natural killer activity by interleukin 2 and poly-I:C, an interferon inducer, is independent of the macrophages in rheumatoid arthritis. These results suggest a deficient natural killer activity in active rheumatoid arthritis and a difference in the modulation of these natural killer cells by macrophages in rheumatoid synovium and normal or rheumatoid arthritis blood.