RATIONALE: Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and associated with a significant burden of comorbidities. Although anemia is associated with adverse outcomes in COPD, its contribution to outcomes in individuals with other comorbid chronic diseases is not well understood. OBJECTIVES: This study examines the association of anemia with outcomes in a large, well-characterized COPD cohort, and attempts to understand the contribution of anemia to outcomes and phenotypes in individuals with other comorbidities. METHODS: Participants with COPD from SPIROMICS (the Subpopulations and Intermediate Outcome Measures in COPD Study) were analyzed in adjusted models to determine the associations of normocytic anemia with clinical outcomes, computed tomographic measures, and biomarkers. Analysis was additionally performed to understand the independence and possible interactions related to cardiac and metabolic comorbidities. RESULTS: A total of 1,789 individuals with COPD from SPIROMICS had data on hemoglobin, and of these 7.5% (n = 135) were found to have normocytic anemia. Anemic participants were older with worse airflow obstruction, a higher proportion of them were African Americans, and they had a higher burden of cardiac and metabolic comorbidities. Anemia was strongly associated with 6-minute walk distance (β, -61.43; 95% confidence interval [CI], -85.11 to -37.75), modified Medical Research Council dyspnea questionnaire (β, 0.27; 95% CI, 0.11-0.44), and St. George's Respiratory Questionnaire (β, 3.90; 95% CI, 1.09-6.71), and these adjusted associations were stronger among those with two or more cardiac and metabolic comorbidities. Anemia was associated with higher levels of serum C-reactive protein, soluble receptor for advanced glycosylation end-products, and epithelial cadherin-1, findings that persisted when in those with a high burden of comorbidities. CONCLUSIONS: Anemia is associated with worse exercise capacity, greater dyspnea, and greater disease severity among adults with COPD, particularly among those with comorbid chronic cardiac and metabolic diseases. The biomarkers found in anemic individuals suggest inflammation, lung tissue injury, and oxidative stress as possible pathways for the adverse correlations of anemia with outcomes in COPD; however, substantial further study is required to better understand these potential mechanisms. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).