Background: CT scan measures of emphysema and airway disease have been correlated with lung function in cohorts of subjects with a range of COPD severity. The contribution of CT scan-assessed airway disease to objective measures of lung function and respiratory symptoms such as dyspnea in severe emphysema is less clear. Methods: Using data from 338 subjects in the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study, densitometric measures of emphysema using a threshold of -950 Hounsfield units (%LAA-950) and airway wall phenotypes of the wall thickness (WT) and the square root of wall area (SRWA) of a 10-mm luminal perimeter airway were calculated for each subject. Linear regression analysis was performed for outcome variables FEV1and percent predicted value of FEV1with CT scan measures of emphysema and airway disease. Results: In univariate analysis, there were significant negative correlations between %LAA-950 and both the WT (r = -0.28, p = 0.0001) and SRWA (r = -0.19, p = 0.0008). Airway wall thickness was weakly but significantly correlated with postbronchodilator FEV1% predicted (R = -0.12, p = 0.02). Multivariate analysis showed significant associations between either WT or SRWA (β = -5.2, p = 0.009; β = -2.6, p = 0.008, respectively) and %LAA-950 (β = -10.6, p = 0.03) with the postbronchodilator FEV1% predicted. Male subjects exhibited significantly thicker airway wall phenotypes (p = 0.007 for WT and p = 0.0006 for SRWA). Conclusions: Airway disease and emphysema detected by CT scanning are inversely related in patients with severe COPD. Airway wall phenotypes were influenced by gender and associated with lung function in subjects with severe emphysema. © 2009 American College of Chest Physicians.