To determine the mechanisms of graft-versus-tumor (GVT) activity in the absence of graft-versus-host disease (GVHD) against a solid tumor, we established two allogeneic bone marrow transplantation models with a murine renal cell carcinoma (RENCA). The addition of 0.3× 10 6 donor CD8+ T cells to the allograft increased the survival of tumor-bearing mice without causing GVHD. The analysis of CD8+ T cells deficient in cytotoxic molecules demonstrated that anti-RENCA activity is dependent on IFN-γ and Fas ligand (FasL), but does not require soluble or membrane-bound TNF-α, perforin, or TRAIL. Recipients of IFN-γ−/− CD8+ T cells are unable to reject RENCA compared with recipients of wild-type CD8+ T cells and, importantly, neither group develops severe GVHD. IFN-γ−/− CD8+ T cells derived from transplanted mice are less able to kill RENCA cells in vitro, while pretreatment of RENCA cells with IFN-γ enhances class I and FasL expression and rescues the lytic capacity of IFN-γ−/− CD8+ T cells. These results demonstrate that the addition of low numbers of selected donor CD8+ T cells to the allograft can mediate GVT activity without lethal GVHD against murine renal cell carcinoma, and this GVT activity is dependent on IFN-γ and FasL.