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Background: The activity of adenosine deaminase decreases in COPD patients and the level of adenosine increases. Decreasing ADA activity in COPD patients can play a significant role in the formation of pulmonary injury. Aim: The aim of this work was to evaluate the changes in serum total ADA level and its isoenzymes (ADA1 and ADA2) in COPD patients with acute exacerbations to determine the possible contribution of these enzymes in COPD. Subjects and Methods: This study was carried out on 60 subjects at Chest Department, Tanta University Hospitals and were divided into three equal groups: group I included 20 healthy non-smokers subjects as control group, group II included 20 asymptomatic smokers and group III included 20 COPD patients with acute exacerbations. Results: There was statistically significant decrease in the activity of ADA total and ADA isoenzyme (ADA1 and ADA2) in COPD patients compared with control group. A positive correlation between ventilatory functions of COPD patients and activity of ADA total and ADA isoenzyme. Conclusion: These data are strongly suggestive of the role of adenosine deaminase activity and its isoenzymes in formation of pulmonary injury in COPD.