The mechanisms of interleukin-12 (IL-12) toxicity were studied in mice using a schedule (murine rIL-12, 400 ng/mouse, intraperitoneally [IP] once daily for 5 days) that markedly reduced body weight and food intake. On day 5, IL-12–treated mice had elevated serum and spleen IFN-γ and tumor necrosis factor (TNF). Serum sTNFR-P75 and corticosterone (CS) were also elevated. IL-12 toxicity was partially prevented by anti–IFN-γ antibodies or dexamethasone (DEX). A pre-dose of IL-12 (200 ng/mouse on day −14) completely prevented the toxicity of subsequent IL-12. The IL-12 predose also inhibited IL-12–induced IFN-γ levels, but did not modify IL-12–induced CS, TNF or sTNFR-P75. A protective effect was observed with a predose of lipopolysaccharide (LPS) or murine recombinant (r)IL-10. The protective effect of the IL-12 predose was reduced by coadministration of anti–IFN-γ, but a predose of murine rIFN-γ was not protective, suggesting that IFN-γ is necessary but not sufficient for the protective effect of IL-12. The IL-12 predose specifically protected against IL-12 toxicity and did not modify LPS toxicity. These data indicate that IL-12 can induce tolerance to its own toxicity, probably through a downregulation of IL-12–induced IFN-γ but independently of endogenous glucocorticoids. IFN-γ, and possibly IL-10, might be important in this tolerance.