Levels of interferon (IFN) were measured in 81 serum samples from 23 patients with systemic lupus erythematosus (SLE) by a plaque-reduction method and correlated retrospectively with clinical records of disease activity, anti-DNA binding, and serum complement measurements. IFN titers were found to correlate with both clinical disease activity and anti-DNA binding, but no relation was found to serum complement. Most (76.6%, 31 of 41) serum samples obtained during periods of active disease contained measureable amounts of IFN, but only 9.1% (2 of 22) of results of tests on samples obtained during periods of disease quiescence were positive (P less than 0.005). Of samples with clearly elevated anti-DNA binding (greater than 40%), 69.7% (23 of 33) had positive results for IFN, but 57.1% (8 of 14) had negative results when the anti-DNA binding was normal (less than 20%) (P less than 0.005). Measurement of serum IFN titers in patients with SLE, therefore, provides another serologic marker of disease activity. Contrary to the findings of previous studies, the IFN found in the present study was characterized as IFN-alpha, or Type I IFN, on the basis of acid stability and neutralization by antibody to IFN-alpha. Of interest are the questions raised about the origin of IFN in the sera of patients with SLE and what role IFN might have in the pathogenesis of the autoimmune disease in view of the many documented immunomodulating effects of IFN.