Patients with chronic obstructive pulmonary disease (COPD) have a reduced quality of life (QoL) and exacerbations that drive health service utilization (HSU). A majority of patients with COPD are managed in primary care. Our objective was to evaluate an integrated disease management, self-management, and structured follow-up intervention (IDM) for high-risk patients with COPD in primary care. This was a one-year multi-center randomized controlled trial. High-risk, exacerbation-prone COPD patients were randomized to IDM provided by a certified respiratory educator and physician, or usual physician care. IDM received case management, self-management education, and skills training. The primary outcome, COPD-related QoL, was measured using the COPD Assessment Test (CAT). Of 180 patients randomized from 8 sites, 81.1% completed the study. Patients were 53.6% women, mean age 68.2 years, post-bronchodilator FEV1 52.8% predicted, and 77.4% were Global Initiative for Obstructive Lung Disease Stage D. QoL-CAT scores improved in IDM patients, 22.6 to 14.8, and worsened in usual care, 19.3 to 22.0, adjusted difference 9.3 (p < 0.001). Secondary outcomes including the Clinical COPD Questionnaire, Bristol Knowledge Questionnaire, and FEV1 demonstrated differential improvements in favor of IDM of 1.29 (p < 0.001), 29.6% (p < 0.001), and 100 mL, respectively (p = 0.016). Compared to usual care, significantly fewer IDM patients had a severe exacerbation, -48.9% (p < 0.001), required an urgent primary care visit for COPD, -30.2% (p < 0.001), or had an emergency department visit, -23.6% (p = 0.001). We conclude that IDM self-management and structured follow-up substantially improved QoL, knowledge, FEV1, reduced severe exacerbations, and HSU, in a high-risk primary care COPD population. Clinicaltrials.gov NCT02343055.