Abstract 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 farmer's 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.