Patients with asthma experience airway structural changes, termed airway remodeling, in response to persistent inflammation. 2-Methoxyestradiol (2-ME) is an anti-angiogenic agent and downregulates hypoxia-inducible factor 1 (HIF-1) and inhibits HIF-1alpha-induced transcriptional activation of vascular endothelial growth factor (VEGF) expression. We hypothesized that 2-ME may interfere with the development of the clinical manifestations of asthma. We used a chronic murine model of allergic airway inflammation with subepithelial fibrosis in BALB/c mice. Mice were sensitized with ovalbumin (OVA) that was administered intraperitoneally at days 0-5 and challenged intratracheally (IT) with OVA on days 12-22. The mice received 2-ME IT at days 24, 26 and 28 and sacrificed at day 32. The sensitized/challenged mice developed an extensive cell inflammatory response of the airways. 2-ME administration significantly reduced the cellular infiltrate in the perivascular and peribronchial lung tissues, reduced goblet mucous production, reduced airway fibrosis and thickness of smooth muscle and blood vessels, and reduced eosinophil infiltration. Mice treated with 2-ME had a significant decrease of HIF-1 and VEGF expression in the perivascular, peribronchial, and interstitium of lung tissues. Collagen IV expression was also significantly reduced in 2-ME treated mice compared to untreated mice. The 2-ME treatment was associated with a significant decrease of OVA-specific IgE antibodies. These findings provide the first indication that IT administration of 2-ME is effective in preventing and reversing antigen-induced airway remodeling in the OVA allergen inflammatory murine model. The potential role of 2-ME in patients is discussed.