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The authors of previous reports have suggested that women are more susceptible to cigarette smoke and to an airway-predominant COPD phenotype rather than an emphysema-predominant COPD phenotype. The purpose of this study was to test for sex differences in COPD phenotypes by using high-resolution CT (HRCT) scanning in male and female smokers with and without COPD.All subjects completed spirometry and answered an epidemiologic respiratory questionnaire. Inspiratory HRCT scans were obtained on 688 smokers enrolled in a family-based study of COPD. Emphysema was assessed by using a density mask with a cutoff of −950 Hounsfield units to calculate the low-attenuation area percentage (LAA%) and by the fractal value D, which is the slope of a power law analysis defining the relationship between the number and size of the emphysematous lesions. Airway wall thickness was assessed by calculating the square root of the airway wall area (SQRTWA) and the percentage of the total airway area taken by the airway wall (WA%) relative to the internal perimeter.Women had a similar FEV1 (women, 65.5% ± 31.9% predicted; men, 62.1% ± 30.4% predicted; p = 0.16) but fewer pack-years of cigarette smoking (women, 37.8 ± 19.7 pack-years; men, 47.8 ± 27.4 pack-years; p < 0.0001). Men had a greater LAA% (24% ± 12% vs 20% ± 11%, respectively; p < 0.0001) and larger emphysematous spaces than women, and these differences persisted after adjusting for covariates (weight, pack-years of smoking, current smoking status, center of enrollment, and FEV1 percent predicted; p = 0.0006). Women had a smaller SQRTWA and WA% after adjusting for covariates (p < 0.0001).Male smokers have more emphysema than female smokers, but female smokers do not show increased wall thickness compared with men.