Female NZB/W F1 mice develop an autoimmune disease similar to human systemic lupus erythematosus (SLE), and ultimately die of glomerulonephritis. Starting at the age of 16 weeks NZB/W F1 mice were treated for a period of 19 weeks with soluble interferon-γ receptor (sIFN-γR), anti-IFN-γ monoclonal antibody (mAb) or IFN-γ. All mice treated with sIFN-γR or anti-IFN-γ mAb were alive 4 weeks after the treatment was discontinued, whereas 50% of mice died in the placebo groups and 78% of the mice died in the IFN-γ-treated group. Histologically, there was severe membrano-proliferative glomerulonephritis in IFN-γ- and placebo-treated mice, and minimal or no mesangioproliferative disease in mice receiving sIFN-γR or anti-IFN-γ mAb. The renal mononuclear infiltrate (T lymphocytes and monocytes), expression of major histocompatibility complex class II antigen and glomerular immunoglobulin and complement deposition were reduced in those mice. These data suggest that an IFN-γ inhibitor, such as the soluble IFN-γR, can be used for SLE therapy in the early stages of the disease.