Tyk2 is activated in response to interleukin-12 (IL-12) and is essential for IL-12–induced T-cell function, including interferon-γ (IFN-γ) production and Th1 cell differentiation. Because IL-12 is a stimulatory factor for natural killer (NK) cell–mediated cytotoxicity, we examined whether tyk2 is required for IL-12–induced NK cell activity. IL-12–induced NK cell activity in cells from tyk2-deficient mice was drastically reduced compared to that in cells from wild-type mice. IL-18 shares its biologic functions with IL-12. However, the molecular mechanism of IL-18 signaling, which activates an IL-1 receptor–associated kinase and nuclear translocation of nuclear factor-κB, is different from that of IL-12. We next examined whether biologic functions induced by IL-18 are affected by the absence of tyk2. NK cell activity and IFN-γ production induced by IL-18 were reduced by the absence of tyk2. Moreover, the synergistic effect of IL-12 and IL-18 for the production of IFN-γ was also abrogated by the absence of tyk2. This was partially due to the absence of any up-regulation of the IL-18 receptor treated with IL-12, and it might suggest the presence of the cross-talk between Jak-Stat and mitogen-activated protein kinase pathways in cytokine signaling.