Rationale: FVC is a difficult maneuver for many patients, and forced expiratory volume in 6 seconds (FEV6) has been proposed as a surrogate for FVC for the diagnosis of chronic obstructive pulmonary disease (COPD). Previous studies have performed head-to-head comparisons of these thresholds but did not examine their relationships with structural lung disease, symptoms, or exacerbations. Objectives: To compare FEV1/FEV 6 with FEV1/FVC in the diagnosis of COPD-related morbidity and structural lung disease as assessed by CT. Methods: We analyzed data from a large multicenter cohort study (COPDGene) that included current and former smokers (age 45-80 yr). Accuracy and concordance between the two ratios indiagnosing structural COPD was compared using CT measures of emphysema and airway disease and COPD-related morbidity to assess how the two ratios compare in defining disease. Results: A total of 10,018 subjects were included. FEV 1/FEV6 showed excellent accuracy in diagnosing airflow obstruction using FEV1/FVC < 0.70 as a reference (area under curve, 0.99; 95% confidence interval [CI], 0.989-0.992; P < 0.001). FEV 1/FEV6 < 0.73 had the best sum of sensitivity (92.1%; 95% CI, 90.8-92.4) and specificity (97.3%; 95% CI, 97.3-98.1). There was excellent agreement between the two diagnostic cutoffs (κ = 0.90; 95% CI, 0.80-0.91; P < 0.001). In comparison with control subjects and those positive by FEV1/FVC alone, subjects positive by FEV1/FEV 6 alone had greater gas trapping and airway wall thickness, worse functional capacity, and a greater number of exacerbations on follow-up. These relationships held true when disease definitions were made using the lower limits of normal. Conclusions: FEV1/FEV6 can be substituted for FEV1/FVC in diagnosing airflow obstruction and may better predict COPD-related pathology and morbidity. Copyright © 2014 by the American Thoracic Society.