Autocrine activation of APC by IL-12 has recently been revealed; we demonstrate here that inducible expression of Stat4 in APC is central to this process. Stat4 is induced in dendritic cells (DC) in a maturation-dependent manner and in macrophages in an activation-dependent manner. Stat4 levels directly correlate with IL-12-dependent IFN-γ production by APC as well as IFN-γ production by DC during Ag presentation. The Th2 cytokines IL-4 and IL-10 suppress Stat4 induction in DC and macrophages when present during maturation and activation, respectively, diminishing IFN-γ production. In contrast, IL-4 has no effect on Stat4 levels in mature DC and actually augments IFN-γ production by DC during Ag presentation, indicating that IL-4 acts differently in a spatiotemporal manner. The functional importance of Stat4 is evident in Stat4−/− DC and macrophages, which fail to produce IFN-γ. Furthermore, Stat4−/− macrophages are defective in NO production in response to IL-12 and are susceptible to Toxoplasma. Autocrine IL-12 signaling is required for high-level IFN-γ production by APC at critical stages in both innate and adaptive immunity, and the control of Stat4 expression is likely an important regulator of this process.