Copyright © 2018 by the American Thoracic Society. Rationale: Quantitative computed tomographic (CT) imaging can aid in chronic obstructive pulmonary disease (COPD) phenotyping. Few studies have identified whether occupational exposures are associated with distinct CT imaging characteristics. Objectives: To examine the association between occupational exposures and CT-measured patterns of disease in the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). Methods: Participants underwent whole-lung multidetector helical CT at full inspiration and expiration. The association between occupational exposures (self-report of exposure to vapors, gas, dust, or fumes [VGDF] at the longest job) and CT metrics of emphysema (percentage of total voxels, 2950 Hounsfield units at total lung capacity), large airways (wall area percent [WAP] and square-root wall area of a single hypothetical airway with an internal perimeter of 10 mm [Pi10]), and small airways (percent air trapping [percent total voxels, 2856 Hounsfield units at residual volume] and parametric response mapping of functional small-airway abnormality [PRM fSAD]) were explored by multivariate linear regression, and for central airway measures by generalized estimating equations to account for multiple measurements per individual. Models were adjusted for age, sex, race, current smoking status, pack-years of smoking, body mass index, and site. Airway measurements were additionally adjusted for total lung volume. Results: A total of 2,736 participants with available occupational exposure data (n = 927 without airflow obstruction and 1,809 with COPD) were included. The mean age was 64 years, 78% were white, and 54% were male. Forty percent reported current smoking, and mean (SD) pack-years was 49.3 (26.9). Mean (SD) post-bronchodilator forced expiratory volume in 1 second (FEV1) was 73 (27) % predicted. Forty-nine percent reported VGDF exposure. VGDF exposure was associated with higher emphysema (b = 1.17; 95% confidence interval [CI], 0.44-1.89), greater large-airway disease as measured by WAP (segmental b = 0.487 [95% CI, 0.320-0.654]; subsegmental b = 0.400 [95% CI, 0.275-0.527]) and Pi10 (b = 0.008; 95% CI, 0.002-0.014), and greater small-airway disease was measured by air trapping (b = 2.60; 95% CI, 1.11-4.09) and was nominally associated with an increase in PRM fSAD (b = 1.45; 95% CI, 0.31-2.60). These findings correspond to higher odds of percent emphysema, WAP, and air trapping above the 95th percentile of measurements in nonsmoking control subjects in individuals reporting VGDF exposure. Conclusions: In an analysis of SPIROMICS participants, we found that VGDF exposure in the longest job was associated with an increase in emphysema, and in large- and small-airway disease, as measured by quantitative CT imaging.