BACKGROUND: Prior research on the risk of depression in chronic obstructive pulmonary disease (COPD) has yielded conflicting results. Furthermore, we have an incomplete understanding of how much depression versus respiratory factors contributes to poor health-related quality of life. METHODS: Among 1202 adults with COPD and 302 demographically matched referents without COPD, depressive symptoms were assessed using the 15-item Geriatric Depression Score. We measured COPD severity using a multifaceted approach, including spirometry, dyspnea, and exercise capacity. We used the Airway Questionnaire 20 and the Physical Component Summary Score to assess respiratory-specific and overall physical quality of life, respectively. RESULTS: In multivariate analysis adjusting for potential confounders including sociodemographics and all examined comorbidities, COPD subjects were at higher risk for depressive symptoms (Geriatric Depression Score >or=6) than referents (odds ratio [OR] 3.6; 95% confidence interval [CI], 2.1-6.1; P <.001). Stratifying COPD subjects by degree of obstruction on spirometry, all subgroups were at increased risk of depressive symptoms relative to referents (P <.001 for all). In multivariate analysis controlling for COPD severity as well as sociodemographics and comorbidities, depressive symptoms were strongly associated with worse respiratory-specific quality of life (OR 3.6; 95% CI, 2.7-4.8; P <.001) and worse overall physical quality of life (OR 2.4; 95% CI, 1.8-3.2; P <.001). CONCLUSIONS: Patients with COPD are at significantly higher risk of having depressive symptoms than referents. Such symptoms are strongly associated with worse respiratory-specific and overall physical health-related quality of life, even after taking COPD severity into account.