Interleukin-27 (IL-27) supports proliferation of naive CD4⁺ T cells and enhances interferon-γ (IFN-γ) production by activated T cells and natural killer (NK) cells. We report here that IL-27 induces Stat1 and Stat3 phosphorylation and activation in human and murine cell lines and primary human T cells. IL-27 also induces T-Bet, a Stat1-dependent gene crucial to Th1 cell commitment. Similarly, IFN-α activates Stat1 and Stat3 and T-Bet expression in naive T cells. Induction of T-Bet results in upregulation of IL-12Rβ2 on naive T cells, which is essential for responsiveness to IL-12 and differentiation to a Th1 phenotype. Both IL-27 and IFN-α induce expression of IL-12Rβ2 in T cells. In contrast, IFN-γ, which activates Stat1 but not Stat3, induces expression of T-Bet but not IL-12Rβ2 in naive T cells. We propose that IL-27 and IFN-α are important for early Th1 commitment and act upstream of IL-12 and IFN-γ in this pathway.