T-bet plays a critical role in controlling IFNγ expression, Th1 polarization, and CD8 cytolytic development. Its regulation has been demonstrated to be mostly IFNγ/Stat1 dependent while IL-12/Stat4 independent. Here we show that IL-12/Stat4 binds to a distant highly conserved STAT-responsive T-bet enhancer, and induces IFNγ/Stat1-independent T-bet expression in CD8 T cells. Luciferase reporter assay showed that both Stat4 and Stat1 activate reporter gene expression from constructs containing a wild-type but not mutated T-bet enhancer. Studies in virus-infected mice demonstrated that the IL-12/Stat4/T-bet cascade operates in vivo and regulates IFNγ in CD8 T cells. Together, we provide a novel mechanism for T-bet regulation, and suggest that IL-12/Stat4/T-bet play an important role in CD8 effector responses.