We investigated the role of interferon (IFN) regulatory factor-2 (IRF- 2) as an oncoprotein in vivo; opposing endogenous IFN-γ suppression of tumor growth. Using syngeneic IFN-γ knockout mice, we show that endogenous IFN-γ slows growth of the mouse melanoma cell line B16-F10 in immunocompetent mice, suggesting that tumor cell resistance to IFN-γ may lead to greater tumorigenicity. IRF-2 is a nuclear transcription factor induced by IFN-γ that represses numerous IFN-inducible genes; including genes that regulate cell growth, in opposition to the transcriptional activator IRF-1. B16-F10 has a marked growth inhibitory response to IFN-γ in vitro and has very little IRF-2 induction compared with other murine tumor cell lines. We engineered B16-F10 cells to stably overexpress murine IRF-2. In vitro, these transfected cells showed a marked resistance to the growth-inhibitory effect of IFN-γ. In normal mice the IRF-2-transfected cells-grew much faster than control tumors. In syngeneic IFN-γ knockout mice, control cells grew at a rate similar to that of IRF-2-transfected cells, implicating resistance to endogenous IFN-c as playing the major role in enhanced growth of IRF-2- transfected tumors in intact mice. These experiments demonstrate that (1) IRF-2 enhances B16 melanoma growth and increases resistance to IFN-γ in vitro, and (2) IRF-2 opposes the growth suppression mediated by endogenous IFN-γ in vivo.