Background: The mechanisms of smoking tobacco leading to chronic obstructive pulmonary disease (COPD) are beginning to be understood. However, conclusions about the role of blood or lung oxidative stress markers were disparate. Aims: To investigate the oxidative stress in blood or lung associated with tobacco smoke and to evaluate its effect on pulmonary function data and its relation with physical activity. Methods: It is a case-control study. Fifty-four male-smokers of more than five pack-years (PY) and aged 40–60 years were included (29 Non-COPD, 16 COPD). Physical activity score was determined. Blood sample levels of malondialdehyde (MDA), protein-cys-SH (PSH), and Glutathione (GSH) were measured. Fractional exhaled nitric oxide (FeNO) and plethysmographic measurements were performed. Correlation coefficients (r) evaluated the association between oxidative stress markers and independent variables (plethysmographic data and physical activity score). Results: Non-COPD (48±6 years) and COPD (49±5 years) groups had similar tobacco consumption patterns, that is, 27±14 PY versus 30±19 PY, respectively. Compared to the Non-COPD group, the COPD group had significantly lower levels of GSH and PSH, that is, mean±SE were 40±6 versus 25±5 µg/mL and 54±10 versus 26±5 µg/g of hemoglobin, respectively. However, MDA level and FeNO values were similar. In the COPD group, none of the oxidative stress markers was significantly correlated with plethysmographic data or physical activity score. In the Non-COPD group, GSH was significantly correlated with physical activity score (r=0.47) and PSH was significantly correlated with total lung capacity (TLC) (r=−0.50), residual volume (r=0.41), and physical activity score (r=0.62). FeNO was significantly correlated with TLC of the COPD group (r=−0.48). Conclusion: Compared to the Non-COPD group, the COPD group had a marked decrease in blood antioxidant markers (GSH and PSH) but similar blood oxidant (MDA) or lung (FeNO) burden.