Rationale: Racial residential segregation has been associated with worse health outcomes, but the link with chronic obstructive pulmonary disease (COPD) morbidity has not been established. Objectives: To investigate whether racial residential segregation is associated with COPD morbidity among urban Black adults with or at risk of COPD. Methods: Racial residential segregation was assessed using isolation index, based on 2010 decennial census and baseline address, for Black former and current smokers in the multicenter SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), a study of adults with or at risk for COPD. We tested the association between isolation index and respiratory symptoms, physiologic outcomes, imaging parameters, and exacerbation risk among urban Black residents, adjusting for established COPD risk factors, including smoking. Additional mediation analyses were conducted for factors that could lie on the pathway between segregation and COPD outcomes, including individual and neighborhood socioeconomic status, comorbidity burden, depression/anxiety, and ambient pollution. Measurements and Main Results: Among 515 Black participants, those residing in segregated neighborhoods (i.e., isolation index >0.6) had worse COPD Assessment Test score (b = 2.4; 95% confidence interval [CI], 0.7 to 4.0), dyspnea (modified Medical Research Council scale; b = 0.29; 95% CI, 0.10 to 0.47), quality of life (St. George's Respiratory Questionnaire; b = 6.1; 95% CI, 2.3 to 9.9), and cough and sputum (b = 0.8; 95% CI, 0.1 to 1.5); lower FEV1% predicted (b = 27.3; 95% CI, 210.9 to 23.6); higher rate of any and severe exacerbations; and higher percentage emphysema (b = 2.3; 95% CI, 0.7 to 3.9) and air trapping (b = 3.8; 95% CI, 0.6 to 7.1). Adverse associations attenuated with adjustment for potential mediators but remained robust for several outcomes, including dyspnea, FEV1% predicted, percentage emphysema, and air trapping. Conclusions: Racial residential segregation was adversely associated with COPD morbidity among urban Black participants and supports the hypothesis that racial segregation plays a role in explaining health inequities affecting Black communities.