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Acetazolamide is a carbonic anhydrase (CA) inhibitor sometimes used as a respiratory stimulant for patients with chronic obstructive pulmonary disease (COPD) with the goal of improving oxygenation, reducing carbon dioxide retention, and aiding liberation from mechanical ventilation and/or attempting to correct a metabolic alkalosis. However, the net effect of CA inhibition is multifactorial and complex, because CA is inhibited in many tissues that may negatively affect the patient with lung disease. The full impact of acetazolamide and other CA inhibitors depends critically on dosing, age, and pulmonary, renal, hepatic, hematological, and respiratory muscle function and reserves. This review examines the literature and indications for acetazolamide use in patients with COPD dating back to its initial release 6 decades ago. There are very few studies specifically designed to address the population with severe COPD, as such patients were frequently excluded from trials. We therefore discuss the complexity of CA inhibition and its potential benefits and dangers and describe ways in which the pathophysiology of patients with severe COPD puts them at considerable risk for serious adverse consequences. We offer guidance on the careful and rational use of acetazolamide in patients with respiratory disorders.