We previously reported that IL-12, but not IFN-αA/D, induces T helper type (Th) 1 development and STAT4 phosphorylation in murine CD4+ T cells. However, a recent study reported that IFN-αA/D and recombinant murine IFN-αA can induce STAT4 phosphorylation, although more weakly than IL-12, largely in CD8+ rather than CD4+ T cells. That report did not examine Th1 development or directly demonstrate induction of IFN-γ by IFN-α. To address these differences, we compared IFN-α A/D, murine IFN-αA, and IL-12 for STAT4 phosphorylation, formation of active nuclear DNA binding complexes, induction of Th1 development, and production of IFN-γ in murine CD4+ T cells. IFN-αA induced detectable STAT4 phosphorylation, although at significantly lower levels than induced by IL-12. Furthermore, in contrast to IL-12, IFN-αA failed to induce Th1 development or the formation of DNA binding complexes or to synergize with IL-18 for induction of IFN-γ production. STAT1-deficient CD4+ T cells showed increased IFN-αA-induced STAT4 phosphorylation but still exhibited significantly lower amounts of cytokine-induced IFN-γ compared to IL-12. In summary, these results suggest that in contrast to IL-12, IFN-αA does not play a functionally significant role in meditating the STAT4-dependent induction of Th1 development or IFN-γ production in CD4+ T cells.