Transforming growth factor beta (TGFbeta) is an immunosuppressive cytokine that contributes to the immunological escape of tumor cells. In a previous study we demonstrated that inhibition of TGFbeta production by EMT6 murine mammary tumor cells expressing an antisense TGF-beta transgene reduces their tumorigenicity. On the basis of this observation we hypothesized that down-regulation of TGFbeta production coupled with interferon gamma (IFNgamma) stimulation would induce an immune response superior to that generated by either strategy alone. In this study, EMT6 tumor cells expressing antisense TGFbeta were transduced with the murine IFNgamma gene. Tumor cells expressing either or both transgenes grew more slowly than mock-transduced tumors. Dual-transgene-expressing tumor cells were more immunogenic than tumor cells expressing either transgene alone. Studies in mice depleted of T cell subsets indicated that CD8+ T cells are the primary effectors of the antitumor activity observed. These results suggest that down-regulation of immunosuppression combined with cytokine-mediated immune augmentation is a useful strategy to improve antitumor immunity.