Oxidative damage caused by oxygen free radicals from activated phagocytes contributes to the pathology of arthritis. The present study evaluates the activity of NADPH oxidase of neutrophils and monocytes from patients suffering from various inflammatory and autoimmune rheumatic disease. Production rates of reactive oxygen species [ROS] of neutrophils and monocytes from rheumatic patients are compared to those of healthy controls and non rheumatic disease controls and correlated with the plasma levels of tumor necrosis factor alpha, C-reactive protein and the sedimentation rates of erythrocytes. There was a two- to eightfold increase in phagocytic superoxide production in rheumatic patients, when compared to healthy subjects or patients with non-rheumatic internal diseases [p < 0.005]. The enhanced NADPH oxidase-dependent superoxide generation correlated well with elevated levels of tumor necrosis factor alpha [TNF-alpha] in plasma [p = 0.005], suggesting a causal relation. There was no correlation with the plasma levels of C-reactive protein and a weak though significant correlation with the sedimentation rates of erythrocytes [p = 0.043]. Removal of circulating TNF-alpha by dialysis of patients blood and inhibition of NADPH oxidase by prednisolone treatment normalized elevated ROS production to the levels of healthy controls and correlated with the clinical improvements. Our data support the hypothesis of a central role for TNF-alpha during the development of arthritis. The chemiluminescence assay described here may be useful as a convenient screen and as a potential follow up procedure for individual patients with rheumatic diseases.