Rationale: Current practice guidelines recommend pulmonary rehabilitation as an adjunct to standard pharmacologic therapy for individuals with moderate to severe chronic obstructive pulmonary disease (COPD). Whether pulmonary rehabilitation benefits all subjects with COPD independent of baseline disease burden is not known. Objectives: To test whether pulmonary rehabilitation benefits patients with COPD independent of baseline exercise capacity, dyspnea, and lung function. Methods: Data from a prospectively maintained database of participants with COPD enrolled in pulmonary rehabilitation at the University of Alabama at Birmingham from 1996 to 2013 were retrospectively analyzed. Subjects were divided into four quartiles based on their baseline level of dyspnea as assessed by the San Diego Shortness of Breath Questionnaire at the initial visit. Similar quartiles were assessed for FEV1 percent predicted as well as the 6-minute-walk distance (6MWD). The primary outcome was the change in quality of life as measured by the 36-item Short Form Health Survey (SF-36). Secondary outcomes were change in dyspnea, 6MWD, and depression scores assessed using the Beck Depression Inventory-II. Differences between baseline and final scores were compared using paired t tests and across quartiles using analysis of variance. Measurements and Main Results: A total of 229 subjects were included. Their mean age was 66.5 (SD, 9) years. Ninety-one (40%) were female, and 42 (18%) were African American. The mean FEV1 percent predicted was 46.3% (20.0%). On completion of pulmonary rehabilitation, clinically significant improvements were seen in most components of SF-36: physical function, 11.5 (95% confidence interval [CI], 7.4-15.5; P<0.001); health perception, 2.1 (95% CI, 20.7 to 4.8; P = 0.12); physical role, 16.7 (95% CI, 10.3-23.1; P<0.001); emotional role, 14.7 (95% CI, 7.1-22.3; P<0.001); social function, 16.4 (95% CI, 11.3-21.5; P<0.001); mental health, 5.4 (95%CI, 2.6-8.3; P<0.001); pain, 5 (95%CI, 1-9.1; P = 0.02); vitality, 12.4 (95% CI, 8.8-16.1; P<0.001); and depression, 0.01 (95% CI, 20.11 to 0.07; P = 0.54). There was no difference in improvement in SF-36 across quartiles of San Diego Shortness of Breath Questionnaire, 6MWD, and FEV1 percent predicted. Conclusions: Pulmonary rehabilitation results in significant improvement in quality of life, dyspnea, and functional capacity independent of baseline disease burden.