Differentiation of Ag-specific T cells into IFN-γ producers is essential for protective immunity to intracellular pathogens. In addition to stimulation through the TCR and costimulatory molecules, IFN-γ production is thought to require other inflammatory cytokines. Two such inflammatory cytokines are IL-12 and type I IFN (IFN-I); both can play a role in priming naive T cells to produce IFN-γ in vitro. However, their role in priming Ag-specific T cells for IFN-γ production during experimental infection in vivo is less clear. In this study, we examine the requirements for IL-12 and IFN-I, either individually or in combination, for priming Ag-specific T cell IFN-γ production after Listeria monocytogenes (Lm) infection. Surprisingly, neither individual nor combined defects in IL-12 or IFN-I signaling altered IFN-γ production by Ag-specific CD8 T cells after Lm infection. In contrast, individual defects in either IL-12 or IFN-I signaling conferred partial (∼ 50%) reductions, whereas combined deficiency in both IL-12 and IFN-I signaling conferred more dramatic (75–95%) reductions in IFN-γ production by Ag-specific CD4 T cells. The additive effects of IL-12 and IFN-I signaling on IFN-γ production by CD4 T cells were further demonstrated by adoptive transfer of transgenic IFN-IR+/+ and IFN-IR−/− CD4 T cells into normal and IL-12-deficient mice, and infection with rLm. These results demonstrate an important dichotomy between the signals required for priming IFN-γ production by CD4 and CD8 T cells in response to bacterial infection.