The factors responsible for abnormal B-cell activation in systemic lupus erythematosus (SLE) are incompletely understood. This study tested the hypothesis that the abnormal B-cell activation observed in human SLE may be due to an augmented response to a helper signal. We demonstrated that non-T cells from 10 of 19 SLE patients increased IgG production in response to interferon-gamma (IFN-gamma) by a mean factor of 20.9 +/- 3.9 over resting levels, while controls stimulated a mean factor of 3.0 +/- 0.5 (P less than 0.005). We found no relationship of IFN-gamma responsiveness to disease activity. Serotyping for HLA A, B, C, and D loci suggested that the hyperresponsiveness may be genetically linked to HLA-Cw7. We conclude that IFN-gamma may contribute to the development and perpetuation of SLE in a subset of patients with SLE.