In this study, we show that sera from 2 of 13 patients with clinically active systemic lupus erythematosus (SLE) contained anti-interferon alpha (anti-IFN alpha) antibody. In contrast, anti-IFN alpha activity was not detected in sera from patients with clinically inactive SLE, rheumatoid arthritis (RA), Sjögren's syndrome, or in normal individuals. None of the sera exhibited anti-IFN gamma activity. These studies show that anti-IFN antibody, like IFN itself, is most frequently observed in patients with clinically active SLE. It is also possible that the presence of IFN-anti-IFN complexes may contribute, in part, to the pathogenesis of this disease.