These experiments were performed to determine whether the absence of donor-derived IFN-γ would influence the outcome of acute graft-vs-host disease (GVHD). Graft-vs-host reactions were induced in B6D2F 1 hybrids using grafts from either IFN-γ gene knockout (gko) or wild-type, C57BL/6J, parental strain donors. GVHD was equally lethal in both groups, but IFN-γ gko graft recipients developed a more protracted form of the disease. These mice developed early wasting that persisted until death. IFN-γ was present in spleen cell cultures from wild-type graft recipients, but was absent in cultures from IFN-γ gko graft recipients. Both recipient groups showed macrophage priming for LPS-induced TNF-α release. Engraftment of donor-derived CD4+ and CD8+ cells was greater in IFN-γ gko graft recipients. Pathologic changes in IFN-γ gko graft recipients were different from those typically seen in acute GVHD. The syndrome developing in IFN-γ gko recipients consisted of patchy alopecia, corneal dryness and clouding, and lymphocytic infiltration of the liver, pancreas, salivary gland, lung, and kidney. Lymphocytic infiltrates were also present in the epidermis and the epithelium of both bile and salivary gland ducts. Some of the lesions closely resembled those seen in the “sicca”/Sjogren’s-like syndrome associated with chronic GVHD; however, there was no evidence of immune complex deposition in the kidney. These results indicate that GVHD in IFN-γ gko graft recipients shares many features with acute GVHD, but both the duration of the disease and its pathologic manifestations are different. Our results suggest that IFN-γ plays a significant role in the pathogenesis of acute GVHD by increasing the rate at which mortality develops.