Background: The hallmark of COPD is airflow obstruction, but this can develop on the basis of airway disease, emphysema, or both. There are gender differences in the natural history of COPD, and these may in part be explained by differences in the pathophysiology of airflow obstruction. We aimed to determine if there are gender differences in the severity of CT emphysema among COPD patients. Methods: Current and former smokers enrolled in the National Lung Screening Trial (NLST) at the University of Alabama at Birmingham were recruited at the time of an annual screening CT examination. We recorded demographics and smoking history, and subjects performed spirometry. Subjects were classified into modified (prebronchodilator) Global Initiative for Chronic Obstructive Lung Disease stages, and their CT scans were analyzed to determine regional and total emphysema (defined as the percentage of low attenuation areas [LAA%]; < -950 Hounsfield units). Differences between genders were examined, and univariate and multivariate predictors of LAA% were determined. Results: A total of 396 subjects participated. Men had more regional and total CT emphysema at all stages of COPD than women (stage 0, 3.9% vs 2.4%, p = 0.001; stage I, 7.0% vs 3.7%, p = 0.015; stage II, 7.8% vs 5.5%, p = 0.063; stages HI/IV, 15.8% vs 8.7%, p = 0.024). In multivariate regression analysis, only gender (p < 0.001) and FEV1/FVC ratio (p < 0.001) predicted total LAA%. Conclusions: At all stages of COPD severity, men have more CT emphysema than women. This difference in radiologic expression may in part explain gender differences in the presentation and natural history of COPD.