Abstract Although IFN-γ is required for resolution of Listeria monocytogenes infection, the identities of the IFN-γ–responsive cells that initiate the process remain unclear. We addressed this question using novel mice with conditional loss of IFN-γR (IFNGR1). Itgax-cre+Ifngr1f/f mice with selective IFN-γ unresponsiveness in CD8α+ dendritic cells displayed increased susceptibility to infection. This phenotype was due to the inability of IFN-γ–unresponsive CD8α+ dendritic cells to produce the initial burst of IL-12 induced by IFN-γ from TNF-α–activated NK/NKT cells. The defect in early IL-12 production resulted in increased IL-4 production that established a myeloid cell environment favoring Listeria growth. Neutralization of IL-4 restored Listeria resistance in Itgax-cre+Ifngr1f/f mice. We also found that Itgax-cre+Ifngr1f/f mice survived infection with low-dose Listeria as the result of a second wave of IL-12 produced by Ly6Chi monocytes. Thus, an IFN-γ–driven cascade involving CD8α+ dendritic cells and NK/NKT cells induces the rapid production of IL-12 that initiates the anti-Listeria response.