© 2020 Cooper et al. Rationale: Some COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype. Objective: To define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death. Methods: We analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls). Measurements: We defined respiratory disability by ≥4 of 7 criteria: mMRC dyspnea scale ≥3; Veterans Specific Activity Questionnaire <5; 6-minute walking distance <250 m; St George’s Respiratory Questionnaire activity domain >60; COPD Assessment Test >20; fatigue (FACIT-F Trial Outcome Index) <50; SF-12 < 20. Results: Using these criteria, respiratory disability was identified in 315 (13.5%) participants (52.1% female). Frequencies were severe COPD 34.5%; mild-moderate COPD 11.2%; smokers without obstruction 5.2% and never-smokers 2.1%. Compared with others, participants with disability had more emphysema (13.2 vs. 6.6%) and air-trapping (37.0 vs. 21.6%) on HRCT (P<0.0001). Using principal components analysis to derive a disability score, two factors explained 71% of variance, and a cut point −1.0 reliably identified disability. This disability score independently predicted future exacerbations (ß=0.34; CI 0.12, 0.64; P=0.003) and death (HR 2.97; CI 1.54, 5.75; P=0.001). Thus, participants with disability by this criterion had almost three times greater mortality compared to those without disability. Conclusion: Our novel SPIROMICS respiratory disability score in COPD was associated with worse airflow obstruction as well as airway wall thickening, lung parenchymal destruc-tion and certain inflammatory biomarkers. The disability score also proved to be an independent predictor of future exacerbations and death. These findings validate disability as an important phenotype in the spectrum of COPD.