Rationale and Objectives Many patients with chronic obstructive pulmonary disease (COPD) have marked discordance between forced expiratory volume in 1 second (FEV1) and degree of emphysema on computed tomography (CT). Biomechanical differences between these patients have not been studied. We aimed to identify reasons for the discordance between CT and spirometry in some patients with COPD. Materials and Methods Subjects with Global initiative for chronic Obstructive Lung Disease stages I–IV from a large multicenter study (The Genetic Epidemiology of COPD) were arranged by percentiles of %predicted FEV1 and emphysema on CT. Three categories were created using differences in percentiles: Catspir with predominant airflow obstruction/minimal emphysema, CatCT with predominant emphysema/minimal airflow obstruction, and Catmatched with matched FEV1 and emphysema. Image registration was used to derive Jacobian determinants, a measure of lung elasticity, anisotropy, and strain tensors, to assess biomechanical differences between groups. Regression models were created with the previously mentioned categories as outcome variable, adjusting for demographics, scanner type, quantitative CT-derived emphysema, gas trapping, and airway thickness (model 1), and after adding biomechanical CT metrics (model 2). Results Jacobian determinants, anisotropy, and strain tensors were strongly associated with FEV1. With Catmatched as control, model 2 predicted Catspir and CatCT better than model 1 (Akaike information criterion 255.8 vs. 320.8). In addition to demographics, the strongest independent predictors of FEV1 were Jacobian mean (β = 1.60,95%confidence intervals [CI] = 1.16 to 1.98; P < 0.001), coefficient of variation (CV) of Jacobian (β = 1.45,95%CI = 0.86 to 2.03; P < 0.001), and CV of strain (β = 1.82,95%CI = 0.68 to 2.95; P = 0.001). CVs of Jacobian and strain are both potential markers of biomechanical lung heterogeneity. Conclusions CT-derived measures of lung mechanics improve the link between quantitative CT and spirometry, offering the potential for new insights into the linkage between regional parenchymal destruction and global decrement in lung function in patients with COPD.