T-lymphocyte-mediated immunosuppression has been described in several animal models and in man. In animal models. T-cell-mediated immunosuppression can hasten the development of cancers, permit the growth of tumors in immunocompetent hosts, and inhibit otherwise effective antitumor immunotherapy. Cyclophosphamide can abrogate the T-cell-mediated immunosuppression. However, inappropriately administered cyclophosphamide can adversely affect antitumor immunity. On the basis of data showing that interferon alpha/beta (IFN alpha/beta) and IFN beta selectively abrogate the T-cell-mediated dinitrofluorobenzene-specific suppressor function, we investigated the efficacy of purified murine IFN alpha/beta in manipulating tumor-induced T-cell-mediated immunosuppression in the well-characterized P815 mastocytoma model. In this model, generation of cytotoxicity in vitro and its inhibition by T cells correlates with antitumor immunity in vivo. We report that IFN alpha/beta selectively diminishes the generation of tumor-induced suppressor activity.