Vascular endothelial growth factor (VEGF) plays as a pro-inflammatory mediator as well as a vascular permeability factor in bronchial asthma. The Insulin-like growth factor (IGF) binding proteins (IGFBPs), especially IGFBP-3, display distinctive properties and can interfere with various biological processes. In this study, an ovalbumin (OVA)-induced murine model of allergic airway disease was used to investigate which mechanism is implicated in the preventive and therapeutic actions of IGFBP-3 administered exogenously on allergen-induced bronchial inflammation, focusing on regulation of VEGF expression. Recombinant human IGFBP-3 substantially attenuated the increases in hypoxia inducible factor (HIF)-a activity, IGF-I pro-duction, and VEGF protein levels in the lung of the mice. In addition, the blockade of IGF-I action decreased the OVA-induced VEGF expression, airway inflammation, and bronchial hyperresponsiveness. The administration of recombinant human IGFBP-3 or CBO-P11 also reduced significantly increases of inflammatory cells, airway hyper-responsiveness, levels of Th2 cytokines, and vascular permeability in the lung of OVA-inhaled mice. Moreover, when recombinant human IGFBP-3 was administered after completion of OVA inhalation, these therapeutic effects of IGFBP-3 were also observed. These results in-dicate that IGFBP-3 administered exogenously may attenuate antigen-induced airway inflammation and hyper-responsiveness through modulation of vascular leakage and VEGF expression mediated by HIF-1a/HIF-2a signaling as well as IGF-I action in allergic airway disease.