Background: Chronic obstructive pulmonary disease (COPD) is a pathology, which leads to an irreversible and progressive reduction of the airflow, usually caused by smoking, but only present in 25% of smokers. Some mechanisms involved in the onset and progression of the disease are local and systemic factors such as inflammation, exacerbated immune response and the appearance of oxidative stress. For all these reasons, the use of oxidative stress parameters as progression markers or even as a way to monitor the response of any kind of non-pharmacological interventions, like the use of pulmonary rehabilitation (PR), is feasible. Aims: The study aims to determine markers of oxidative stress levels in plasma and erythrocytes in patients with COPD through the application of a PR protocol. Methods: The study included 25 patients diagnosed with COPD according to the GOLD criteria with a medical indication of PR and attendance at the gym in San José Hospital, Santiago, Chile. Blood samples were obtained before the start of the protocol, in the 10th session, and at the end of the protocol (20th session). These samples were stored for oxidative stress determinations: FRAP (ferric reducing ability of plasma), F2-isoprostanes, reduced (GSH)/oxidized (GSSG) ratio and antioxidant enzyme activity in the erythrocyte. In all stages, associations between events and clinical parameters in patients have been observed. The clinical parameters assessed were the six-minute walking test (6MWT), maximal inspiratory and expiratory pressure, the BODE index and Saint George’s respiratory questionnaire, which includes quality of life. Results: The intracellular and extracellular capacity (GSH/GSSG and FRAP) in patients in PR at the 10th session were 53.1 and 34% higher than basal values, respectively. Only the GSH/GSSG ratio was 38.2% lower at the 20th session, related in part with higher plasma and erythrocyte lipid peroxidation at baseline. This could be due to the high concentration of reactive oxygen species in the first sessions, which has been reported in the literature as the acute effect of controlled exercise. Blood lipid peroxidation was 43.34 and 58.34% lower at the 10th and 20th sessions, respectively, demonstrating the improvements in the oxidative parameters with long-term exercise. With respect to oxidative enzyme activity, superoxide dismutase and catalase showed higher values of activity at the 10th and 20th sessions compared to the baseline. In the clinical parameters of the PR, significant changes were found in the BODE index and Saint George’s questionnaire, with these results being associated with a less predictive mortality score and a better understanding of the disease. This may be because the patients achieved longer distances in the 6MWT and better understood the disease at the end of the PR. Conclusion: The goal of this study was to contribute to the pathophysiological basis for further research on COPD patients, a disease of high prevalence in Chile. This study could support the basis for non-pharmacological strategies such a PR.