Mouse interferon-gamma (MuIFN-gamma) can cause the rejection of malignant cells in vivo. The evidence presented here in support of this claim includes, first, that spontaneous regression of MSC sarcomas was associated with high intratumoral concentrations of endogenously-produced MuIFN-gamma. By contrast, progressively growing, lethal neoplasms of the same kind invariably contained very little IFN-gamma. Second, spontaneously regressing MSC sarcomas were converted into progressively growing, lethal neoplasms by injecting mice with a monoclonal antibody that neutralized the biological effects of endogenous IFN-gamma. Another monoclonal antibody that bound to, but did not neutralize, mouse IFN-gamma had no effect on the course of tumor regression. Together, these data causally relate MuIFN-gamma to the successful rejection of malignant cells in vivo. They also suggest that findings of poor therapeutic efficacy for IFN-gamma are probably attributable to problems other than an intrinsic lack in the biological activity of the lymphokine.