To elucidate the characterization of peripheral natural killer (NK) cells in patients with rheumatoid arthritis (RA), we investigated the NK cell activity, the expression of NK cell activating receptors and intracellular molecules. The NK activity was analyzed in 27 RA patients, 22 primary Sjögren's syndrome (SS) patients, and 15 healthy individuals using the (51)Chrominium release assay. The expression of NK cell activating receptors (NKG2D, CD244, CD2, and CD16) and intracellular molecules (granzyme B, perforin, and TCR zeta chain) in CD3-CD56+ cells were characterized by flow cytometry. The serum cytokine levels (IL-6, TNFalpha, and IL-18) were measured using ELISA. Both the NK cell activity and the activity on a per-cell basis were observed to significantly decrease in the RA patients in comparison to the controls. The expression of NKG2D and CD244 also significantly decreased in both the RA and primary SS patients, whereas the significant decrease in the CD16 expression was only observed in the RA patients. The titer of the serum IL-6, TNFalpha, and IL-18 was significantly higher in the RA patients than in the controls. These data suggest that a low NK activity on a per-cell basis might therefore contribute to an impaired NK activity in the patients with RA.