Natural killer (NK) cell number and function were determined in 69 systemic sclerosis (SSc) patients (41 with diffuse cutaneous SSc, 24 with limited cutaneous SSc, and 4 with scleroderma in an overlap syndrome). The results were compared with those obtained from 5 patients with Raynaud's disease and from 27 normal controls. Natural and antibody-dependent killing was reduced in the total group of SSc patients compared with controls, but these differences were primarily attributable to patients with the diffuse form of the disease who were seen early in their illness (less than 5 years after onset). NK cell numbers were not significantly reduced in patients compared with controls, although lower numbers were observed in individuals with early diffuse disease. Other clinical parameters, such as treatment with D-penicillamine or the presence of scleroderma-specific autoantibodies, did not exert an independent effect on NK cell function. These findings suggest a possible central role for NK cells in the pathogenesis of SSc.