Using a neutralizing monoclonal antibody specific for murine IFNy we show that endogenously produced IFNγ plays an obligate role in mediating LPS-induced rejection of the Meth A fibrosarcoma tumor in syngeneic BALE/c mice. To examine the cellular targets of IFNγ action, we generated IFNγ-insensitive tumor cells by stably overexpressing in Meth A a truncated dominant negative form of the murine IFNγ receptor a chain. When implanted in BALB/c mice, IFNγ-insensitive Meth A cells displayed enhanced tumorigenicity compared with control Meth A cells and were not rejected when tumor-bearing mice were treated with concentrations of LPS that eliminated control tumors. In Meth A immune mice, IFNγ-sensitive Meth A did not establish tumors while IFNγ-insensitive tumors grew in a progressive manner. In addition, the IFNγ-insensitive tumor cells were unable to elicit strong protective immunity to subsequent wild-type tumor challenge. These results show that IFNγ has direct effects on tumor cell immunogenicity and thus plays an important role in promoting tumor cell recognition and elimination.