Background: Oxidative stress has been suggested in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) with an additional burden of diabetes, hypertension and cardiovascular disease. In the present study, we investigated erythrocyte antioxidant enzymes activities in correlation to COPD severity and COPD comorbidities. Methods: One hundred twenty seven subjects with COPD and 59 healthy controls participated in this study. COPD severity was done based on the Global Initiative for Chronic Obstructive Lung Disease criteria. The erythrocytes enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR) and total antioxidant status (TAS) were measured with spectrophotometric method. Results: COPD patients showed significant decrease in TAS (p > 0.05), GST (p < 0.001) and GPx (p < 0.01) activities with progression of the disease. In patients, FEV 1 was negatively correlated with SOD, GR and positively correlated with GST and GPx activities. Further, multivariate logistic regression analysis revealed GST (OR = 0.93; 95% CI = -0.10 -0.01; p < 0.01) , GPx (OR = 0.98; 95% CI = -0.03 -0.00; p < 0.05) and TAS (OR = 0.95; 95% CI = -0.08 -0.00; p < 0.05) were independently associated with FEV 1 in GOLD stage IV and GST (OR = 1.11; 95% CI = 0.04-0.18; p < 0.001) in GOLD stage II. Regression analysis confirmed a significant difference in GPx activity in COPD -type 2 diabetes (OR = 0.04; 95% CI = -6.60 -0.53; P = 0.09), and GST activity in COPD -cardiovascular disease (OR = 2.51; 95% CI = 0.00 -1.84; p < 0.05) patients when compared to patients without comorbidities. Conclusion: A significant decline in lung function may be associated with altered antioxidant enzyme activity due to the strong correlation between GST and GPx with COPD severity. Our results also indicate that erythrocytes GST and GPX activities are significantly associated with comorbidities, but only in COPD patients with type 2 diabetes and cardiovascular disease.