Background: Cigarette smoke and smoking-induced infl ammation decrease cystic fi brosis transmembrane conductance regulator (CFTR) activity and mucociliary transport in the nasal airway and cultured bronchial epithelial cells. This raises the possibility that lower airway CFTR dysfunction may contribute to the pathophysiology of COPD. We compared lower airway CFTR activity in current and former smokers with COPD, current smokers without COPD, and lifelong nonsmokers to examine the relationships between clinical characteristics and CFTR expression and function. Methods: Demographic, spirometry, and symptom questionnaire data were collected. CFTR activity was determined by nasal potential difference (NPD) and lower airway potential difference (LAPD) assays. The primary measure of CFTR function was the total change in chloride transport (D chloride-free isoproterenol). CFTR protein expression in endobronchial biopsy specimens was measured by Western blot. Results: Compared with healthy nonsmokers (n = 11), current smokers (n = 17) showed a signifi cant reduction in LAPD CFTR activity (D chloride-free isoproterenol,-8.70 mV vs-15.9 mV; P = .003). Similar reductions were observed in smokers with and without COPD. Former smokers with COPD (n = 7) showed a nonsignifi cant reduction in chloride conductance (-12.7 mV). A similar pattern was observed for CFTR protein expression. Univariate analysis demonstrated correlations between LAPD CFTR activity and current smoking, the presence of chronic bronchitis, and dyspnea scores. Conclusions: Smokers with and without COPD have reduced lower airway CFTR activity compared with healthy nonsmokers, and this fi nding correlates with disease phenotype. Acquired CFTR dysfunction may contribute to COPD pathogenesis. © 2013 American College of Chest Physicians.