Distinct forms of graft-vs-host disease (GVHD) occur in (C57B1/6 x DBA/2)F1 (BDF1) mice inoculated with either C57B1/6 or DBA/2 parental spleen cells, and it has been suggested that this reflects differential activation of CD4+ Th cell subsets. Transfer of B6 cells produces an acute GVHD, during which an early period of lymphoid hyperplasia precedes immunosuppression, weight loss, and mortality, and a Th1 pattern of cytokines is produced. Conversely, transfer of DBA/2 cells induces a chronic GVHD, in which no weight loss or mortality is observed, but an autoimmune, SLE-like GVHD develops in association with a Th2 pattern of cytokines. Recent work indicates that IL-12 plays a central role in the polarization of Th cell-dependent responses, and here we have examined its role in polarizing GVHD, by administering or depleting IL-12 during the afferent phase of both the acute and chronic forms of GVHD in BDF1 mice. In vivo neutralization of endogenous IL-12 ameliorated acute GVHD, in association with reduced splenic NK cell activity, IFN-gamma production, immunosuppression, weight loss, and mortality. Conversely, administration of exogenous murine rIL-12 exacerbates this disease and converts the chronic GVHD into a lethal acute GVHD-like syndrome. These results indicate that IL-12 plays an important role in the development of acute, but not chronic, GVHD and suggest that differential production of IL-12 early in the disease may underlie these distinct outcomes of the GVHD in BDF1 mice injected with different parental cells.