In airway remodeling that occurs in association with chronic obstructive pulmonary disease (COPD), the relationship between the subepithelium and structural changes of the bronchial epithelium is not well defined. To investigate whether the subepithelium and epithelium undergo remodeling as an integrated unit, we performed morphological examination of 55 bronchial biopsy specimens obtained from explanted or resected lungs from tobacco smokers with COPD. Our results indicate that reticular basement membrane (RBM) thickness is increased and the subepithelial microvascular bed is reduced in association with progression from the normal epithelium to squamous metaplasia. Subsequent bronchial epithelial transformation to dysplasia is characterized by differential subepithelial remodeling with normalization of RBM thickness and subepithelial blood vessel density. Because fibrous remodeling of the subepithelium could limit delivery of nutrients and oxygen to the epithelium, we assessed expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase IX (CA IX) as markers of cellular hypoxia. The number of HIF-1alpha-positive epithelial cells increased with progression of epithelial structural changes, RBM thickness, and reduction in blood vessels in the subepithelium. These findings suggest that the HIF-1alpha pathway is activated in response to subepithelial remodeling and contributes to progressive premalignant epithelial lesions in the airways of tobacco smokers with chronic airway inflammation.