Abstract Systemic lupus erythematosus (SLE) is characterized by immune abnormalities explained by the overproduction of Th 2cytokines such as autoantibody production and polyclonal B cell activation. We examined the effect of administering a DNA plasmid encoding IL-12 on the lupus-like disease of MRL/MP-lpr/lpr (MRL/lpr) mice. Treatments were delivered intramuscularly every 4 weeks, starting at 4 weeks of age. This intervention significantly inhibited the accumulation of CD4 −CD8 −T cells, and reduced lymphadenopathy and splenomegaly. A significant decrease in serum IgG anti-DNA autoantibody titers was observed, and plasmid IL-12 therapy was also associated with a reduction in the proteinuria and glomerulonephritis characteristic of this disease. Serum IFN-γ level was increased by inoculating IL-12 encoding plasmid, suggesting that the cytokine balance was skewed towards Th 1. The clinical implications of this suppression of autoimmune disease are also discussed.