Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation in the airways, parenchyma and vessels, which can cause a structural remodeling with increased fibrosis that narrows and fixes the airway lumen. Transforming growth factor-β1 (TGF-β1), a multifunctional growth factor, was reported to be increased in the airways of COPD patients. In this study, we hypothesized that polymorphisms in the TGF-β1 gene would be associated with an accelerated rate of decline of forced expiratory volume in 1s (FEV₁). Three polymorphisms, −509 (C→T), +869 (T→C) and +915 (G→C), located in TGF-β1 gene were genotyped. We determined the prevalence of these polymorphisms in 590 continuing smokers who had the fastest ( ) and slowest ( ) rate of decline of lung function from the NHLBI Lung Health Study. There was no association between these TGF-β1 polymorphisms and the rate of decline of FEV₁, but in a post-hoc analysis the genotype distribution at +869 was significantly different between high and low responders to methacholine ( ). These data suggest that the T–C polymorphism at position +869 in the TGF-β1 gene contributes to airway hyperresponsiveness, but not to rapid decline of lung function.