Rationale: Hypersensitivity pneumonitis is mediated by a Th1 immune response. Transcription factor GATA-3 is thought to be a key regulator of Th2 differentiation and thus might play regulatory roles in the pathogenesis of hypersensitivity pneumonitis. Objective: We examined the effect of GATA-3-overexpression on the development of hypersensitivity pneumonitis in mice. Methods: Wild-type C57BL/6 mice and GATA-3-overexpressing mice of the same background were used in this study. Hypersensitivity pneumonitis 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- in wild-type mice. The degree of pulmonary inflammation was much less severe in GATA-3-overexpressing mice. The induction of T-bet and interferon- genes was suppressed, but a significant induction of Th2 cytokines, including interleukin-5 and interleukin-13, was observed in the lungs of GATA-3-overexpressing mice after antigen exposure. Supplementation with recombinant interferon- enhanced lung inflammatory responses in GATA-3-overexpressing mice to the level of wild-type mice. Since antigen-induced interferon- 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 interferon- level. Conclusions: These results indicate that overexpression of GATA-3 attenuates the development of hypersensitivity pneumonitis by correcting the Th1-polarizing condition.