Interleukin (IL)-12 is a potent immunostimulatory cytokine and inducer of Th1 cell activity and of cytotoxic T lymphocyte and natural killer cell function. This cytokine also has anti-tumor activity. Although IL-12 has been shown to be an important pathogenic cytokine in the induction of graft-versus-host disease (GVHD), injection of exogenous IL-12 to murine allogeneic bone marrow transplantation (BMT) recipients paradoxically leads to a significant delay in the onset of GVHD mortality in fully MHC plus multiple minor antigen-mismatched strain combinations, and to complete inhibition of GVHD in a single haplotype-mismatched murine BMT model. IL-12induced inhibition of GVHD is associated with reduced donor T cell activation and expansion, in part through an interferon (1FN)-y-mediated mechanism. Fas-mediated apoptosis of donor T cells also plays a significant role in IL-12-induced GVHD protection. Importantly, IL-12 preserves the graft-versus-leukemia (GVL) effect of allogeneic CD8 T cells against EL4, a host-type leukemiaAymphoma, while inhibiting GVHD. Like the protective effect against GVHD, the GVL effect in IL-12-treated mice is dependent on IFN-y. Thus, treatment with IL-12 leads to separation of GVHD-promoting and GVL effects of allogeneic BMT via an IFN-y-dependent mechanism.