Natural killer (NK) cell activity and its regulation in synovial fluid (SF), synovial tissue (ST), and peripheral blood (PB) was studied in 23 patients with active rheumatoid arthritis (RA). NK activity was reduced in PB (P less than 0.005), SF (P less than 0.002), and ST of patients with RA compared to the PB of 28 healthy controls. NK activity in SF was inversely correlated with disease activity as measured by erythrocyte sedimentation rate (r = -0.561; P less than 0.02). Poly I:C, an interferon inducer, stimulated NK activity in RA patients' PB and SF and control subjects' PB to similar extents. However, augmentation of NK activity by interleukin-2 was significantly greater in SF than in PB of RA (P less than 0.02). Preincubation of mononuclear cells with indomethacin significantly increased the NK activity of normal and RA PB but had no effect on that of SF. These observations suggest that the NK activity may be reduced in both PB and SF of RA and that functional differences between populations of cells with NK-like activity and/or differences in the control or modulation of NK activity exist between PB and SF.