The immunoregulator human gamma interferon (IFN-gamma) suppressed the spontaneous in vitro synthesis and secretion of anti-DNA antibodies by peripheral blood mononuclear cells of patients with systemic lupus erythematosus (SLE-PBMC). Comparable level of suppression were observed with both natural human IFN-gamma and recombinant derived human IFN-gamma. In addition, the inhibitory effects of human IFN-gamma were completely neutralized by a monoclonal antibody directed against it. Human IFN-gamma also inhibited the antigen induced production of anti-DNA synthesis by SLE-PBMC. Based on the kinetics of inhibition, human IFN-gamma appeared to be acting directly on the B cell. Lastly, human IFN-gamma also suppressed the spontaneous production of IgG and IgM by SLE-PBMC. Our findings support the conclusion that SLE Ig production can be regulated and that human IFN-gamma may be clinically useful in the treatment of SLE as well as other immune complex diseases.