Interleukin (IL)-18 synergizes with IL-12 to promote T helper cell (Th)1 responses. Somewhat paradoxically, IL-18 administration alone strongly induces immunoglobulin (Ig)E production and allergic inflammation, indicating a role for IL-18 in the generation of Th2 responses. The ability of IL-18 to induce IgE is dependent on CD4(+) T cells, IL-4, and signal transducer and activator of transcription (stat)6. Here, we show that IL-18 fails to induce IgE both in CD1d(-/-) mice that lack natural killer T (NKT) cells and in class II-/- mice that lack conventional CD4(+) T cells. However, class II-/- mice reconstituted with conventional CD4(+) T cells show the capacity to produce IgE in response to IL-18. NKT cells express high levels of IL-18 receptor (R)alpha chain and produce significant amounts of IL-4, IL-9, and IL-13, and induce CD40 ligand expression in response to IL-2 and IL-18 stimulation in vitro. In contrast, conventional CD4(+) T cells express low levels of IL-18Ralpha and poorly respond to IL-2 and IL-18. Nevertheless, conventional CD4(+) T cells are essential for B cell IgE responses after the administration of IL-1.8. These findings indicate that NKT cells might be the major source of IL-4 in response to IL-18 administration and that conventional CD4(+) T cells demonstrate their helper function in the presence of NKT cells.