Rationale: Cough is one of the principal symptoms of chronic obstructive pulmonary disease (COPD) but the potential drivers of cough are likely to be multifactorial and poorly understood. Objectives: To quantify cough frequency in an unselected group of subjects with COPD and investigate the relationships between cough, reported sputum production, smoking, pulmonary function, and cellular airway inflammation. Methods: We studied 68 subjects with COPD (mean age, 65.6 ± 6.7 yr; 67.6% male; 23 smokers; 45 ex-smokers) and 24 healthy volunteers (mean age, 57.5 ± 8.9 yr; 37.5% male; 12 smokers; 12 non-smokers). Subjects reported cough severity, cough-specific quality of life, and sputum expectoration and performed spirometry, sputum induction, cough reflex sensitivity to capsaicin, and 24-hour ambulatory cough monitoring. Measurements and Main Results: COPD current smokers had the highest cough rates (median, 9 coughs/h [interquartile range, 4.3-15.6 coughs/h]), almost double that of COPD ex-smokers (4.9 [2.3-8.7] coughs/h; P = 0.018) and healthy smokers (5.3 [1.2-8.3] coughs/h; P = 0.03), whereas healthy volunteers coughed the least (0.7 [0.2-1.4] coughs/h). Cough frequency was not influenced by age or sex and only weakly correlated with cough reflex sensitivity to capsaicin (log C5r=20.36;P=0.004). Reported sputum production, smoking history, and current cigarette consumption strongly predicted cough frequency, explaining 45.1% variance in a general linear model (P <0.001). In subjects producing a sputum sample, cough frequency was related to current cigarette consumption and percentage of sputum neutrophils (P = 0.002). Conclusions: Ambulatory objective monitoring provides novel insights into the determinants of cough in COPD, suggesting sputumproduction, smoking, and airway inflammation may be more important than sensitivity of the cough reflex. Copyright © 2013 by the American Thoracic Society.