OBJECTIVES: The purposes of this study were to evaluate the reference range of quantitative computed tomography (QCT) measures of lung attenuation and airway parameter measurements in healthy nonsmoking adults and to identify sources of variation in those measures and possible means to adjust for them. MATERIALS AND METHODS: Within the COPDGene study, 92 healthy non-Hispanic white nonsmokers (29 men, 63 women; mean [SD] age, 62.7 [9.0] years; mean [SD] body mass index [BMI], 28.1 [5.1] kg/m) underwent volumetric computed tomography (CT) at full inspiration and at the end of a normal expiration. On QCT analysis (Pulmonary Workstation 2, VIDA Diagnostics), inspiratory low-attenuation areas were defined as lung tissue with attenuation values -950 Hounsfield units or less on inspiratory CT (LAAI-950). Expiratory low-attenuation areas were defined as lung tissue -856 Hounsfield units or less on expiratory CT (LAAE-856). We used simple linear regression to determine the impact of age and sex on QCT parameters and multiple regression to assess the additional impact of total lung capacity and functional residual capacity measured by CT (TLCCT and FRCCT), scanner type, and mean tracheal air attenuation. Airways were evaluated using measures of airway wall thickness, inner luminal area, wall area percentage (WA%), and standardized thickness of an airway with inner perimeter of 10 mm (Pi10). RESULTS: Mean (SD) %LAAI-950 was 2.0% (2.7%), and mean (SD) %LAAE-856 was 9.2% (6.8%). Mean (SD) %LAAI-950 was 3.6% (3.2%) in men, compared with 1.3% (2.0%) in women (P < 0.001). The %LAAI-950 did not change significantly with age (P = 0.08) or BMI (P = 0.52). %LAAE-856 did not show any independent relationship with age (P = 0.33), sex (P = 0.70), or BMI (P = 0.32). On multivariate analysis, %LAAI-950 showed a direct relationship to TLCCT (P = 0.002) and an inverse relationship to mean tracheal air attenuation (P = 0.003), and %LAAE-856 was related to age (P = 0.001), FRCCT (P = 0.007), and scanner type (P < 0.001). Multivariate analysis of segmental airways showed that inner luminal area and WA% were significantly related to TLCCT (P < 0.001) and age (0.006). Moreover, WA% was associated with sex (P = 0.05), axial pixel size (P = 0.03), and slice interval (P = 0.04). Lastly, airway wall thickness was strongly influenced by axial pixel size (P < 0.001). CONCLUSIONS: Although the attenuation characteristics of normal lung differ by age and sex, these differences do not persist on multivariate analysis. Potential sources of variation in measurement of attenuation-based QCT parameters include depth of inspiration/expiration and scanner type. Tracheal air attenuation may partially correct variation because of scanner type. Sources of variation in QCT airway measurements may include age, sex, BMI, depth of inspiration, and spatial resolution.