While IL‐18 synergizes with IL‐12 to induce a Th1 immune response, it also promotes a Th2 response. Here we investigate the modulatory role of IL‐18 on the Th1/Th2 cytokine response. The injection of α‐galactosylceramide (α‐GalCer), a ligand for NKT cells, elevated mouse serum levels of both IFN‐γ and IL‐4. When the mice were treated 2 h before α‐GalCer challenge with IL‐18, IFN‐γ production but not IL‐4 production was remarkably up‐regulated. In contrast, pretreatment with IL‐18 6 h before the challenge enhanced IL‐4 production. However, this IL‐18‐enhanced IL‐4 production was not elicited in mice injected with anti‐CD3 Ab. Liver mononuclear cells (MNC) produced a similar cytokine production pattern when MNC from mice treated with IL‐18 either 2 h or 6 h before challenge were stimulated with α‐GalCer in vitro. Expression of SOCS1 and SOCS3 was notably up‐regulated in the liver MNC from mice pretreated 6 h before with IL‐18; in particular, SOCS3 expression was confined to the liver NKT cells. Inhibition of SOCS3 by RNA interference up‐regulated the phosphorylation of STAT3 and suppressed in vitro IL‐4 production by IL‐18‐primed liver MNC stimulated with α‐GalCer, but it did not affect IFN‐γ production. These results suggest that IL‐18 time‐dependently modulates Th1/Th2 cytokine production in ligand‐activated NKT cells by regulating/inducing SOCS3 expression.