Interleukin 21 (IL-21) has recently been identified as a multifunctional cytokine that induces the proliferation of T cells and B cells and differentiation of natural killer cells. To determine whether IL-21 regulates IL-4-mediated immune responses, we examined the effect of IL-21 on antigen-specific IgE production in mice. We also examined the effect of IL-21 on IL-4-induced IgE production from B cells and antigen-induced T-helper 2 (T(h)2) cell differentiation. The in vivo injection of IL-21 prevented antigen-specific IgE but not IgG2a production on immunization. IL-21 did not affect T(h)2 cell differentiation or IL-4 production from CD4(+) T cells but directly inhibited IL-4-induced IgE production from B cells at single-cell levels. Moreover, IL-21 inhibited IL-4-induced germ line C(epsilon) transcription in B cells without the inhibition of signal transducer and activator of transcription 6 (Stat6) activation. Taken together, these results indicate that IL-21 down-regulates IgE production from IL-4-stimulated B cells through the inhibition of germ line C(epsilon) transcription and thus suggest that IL-21 may be useful for the treatment of IgE-dependent allergic diseases.