RATIONALE:: Hypersensitivity pneumonitis (HP) is mediated by a Th1 immune response. Transcription factor GATA binding protein-3 (GATA-3) is believed to be a key regulator of Th2 differentiation and thus might play regulatory roles in the pathogenesis of hypersensitivity pneumonitis (HP). OBJECTIVES:: We examined the effect of GATA-3 overexpression on the development of HP in mice. METHODS:: Wild-type C57BL/6 mice and GATA-3–overexpressing mice of the same background were used in this study. HP was induced by repeated exposure to Saccharopolyspora rectivirgula, the causative antigen of farmerʼs lung. MEASUREMENTS AND MAIN RESULTS:: Antigen exposure resulted in a marked inflammatory response with enhanced pulmonary expression of T-bet and the Th1 cytokine interferon (IFN)-γ in wild-type mice. The degree of pulmonary inflammation was much less severe in GATA-3–overexpressing mice. The induction of T-bet and IFN-γ genes was suppressed, but a significant induction of Th2 cytokines, including IL-5 and IL-13, was observed in the lungs of GATA-3–overexpressing mice after antigen exposure. Supplementation with recombinant IFN-γ enhanced lung inflammatory responses in GATA-3–overexpressing mice to the level of wild-type mice. Because antigen-induced IFN-γ production predominantly occurred in CD4 T cells, nude mice were transferred with CD4 T cells from either wild-type or GATA-3–overexpressing mice and subsequently exposed to antigen. Lung inflammatory responses were significantly lower in nude mice transferred with CD4 T cells from GATA-3–overexpressing mice than in those with wild-type CD4 T cells, with a reduction of lung IFN-γ level. CONCLUSIONS:: These results indicate that overexpression of GATA-3 attenuates the development of HP by correcting the Th1-polarizing condition.