Polarization of CD4⁺ T helper cells toward either a Th1 or Th2 response can significantly influence host immunity to pathogens. IL-4 and IFN-γ are the signature cytokines of Th2 and Th1 cells, respectively. IFN-γ was shown to assist Th1 development by promoting IL-12 and IL-12 receptor expression. So far, direct influence of Th2 cytokine expression by IFN-γ has not been described. We show here that IFN-γ directly suppresses IL-4 gene expression. IRF-1 and IRF-2 induced by IFN-γ bind to three distinct IL-4 promoter sites and function as transcriptional repressors. Our data demonstrate a direct negative feedback of IFN-γ on expression of the Th2 cytokine gene IL-4 and, thus, provide evidence for another important mechanism by which IFNγ assists Th1 and attenuates Th2 responses.