Introduction: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide and has a prevalence of 11.7%. Current treatment focuses on reducing symptoms and exacerbations, as no definitive intervention exists. Regenerative treatments such as mesenchymal stem cell (MSCs) therapy have shown promise in preclinical and clinical studies. This article presents a study protocol to evaluate the efficacy of adipose-derived (AD) MSCs therapy in improving FEV-1 in COPD patients. Methods: A phase III, multicenter, randomized, double-blind, placebo-controlled study is proposed to test the clinical safety and efficacy of AD-MSC therapy in patients with COPD. The population is subjects with COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 (50%≤FEV1<80% predicted) and Group D (two exacerbations or one hospitalization and mMRC>2 or CAT>10). This study aims to evaluate the improvement of FEV1 from baseline to 90 days after AD-MSC infusion. The primary outcome is FEV1-improvement (%) over the baseline for the treatment and placebo groups, assessed on study day 90 vs. baseline (day 0). For the primary outcome, the statistical analysis will use the Mann-Whitney U test to analyze the FEV1 for the treatment and control groups at 90 days against the baseline. Discussion: Aside from symptomatic relief, there is a growing demand for a curative treatment for COPD. The potential of novel AD-MSCs therapies for COPD improvement is currently in early development. Preclinical, phase I, and a few phase II studies for AD-MSCs as a COPD treatment have proven optimistic results. This phase III, randomized, multicenter trial proposes evaluating an alternative treatment for this condition that may improve lung function.