Resistance to tuberculosis (TB) is dependent on the induction of Ag-specific CD4 Th1 T cells capable of expressing IFN-γ. Generation of these T cells is dependent upon IL-12p70, yet other cytokines have also been implicated in this process. One such cytokine, IL-27, augments differentiation of naive T cells toward an IFN-γ-producing phenotype by up-regulating the transcription factor T-bet and promoting expression of the IL-12Rβ2 chain allowing T cells to respond to IL-12p70. We show that the components of IL-27 are induced during TB and that the absence of IL-27 signaling results in an altered disease profile. In the absence of the IL-27R, there is reduced bacterial burden and an increased lymphocytic character to the TB granuloma. Although the number of Ag-specific CD4 IFN-γ-producing cells is unaffected by the absence of the IL-27R, there is a significant decrease in the level of mRNA for IFN-γ and T-bet within the lungs of infected IL-27R−/− mice. Ag-specific CD4 T cells in the lungs of IL-27R−/− also produce less IFN-γ protein per cell. The data show that expression of IL-27 during TB is detrimental to the control of bacteria and that although it does not affect the number of cells capable of producing IFN-γ it does reduce the ability of CD4 T cells to produce large amounts of IFN-γ. Because IFN-γ is detrimental to the survival of effector T cells, we hypothesize that the reduced IFN-γ within the IL-27R−/− lung is responsible for the increased accumulation of lymphocytes within the mycobacterial granuloma.