In Chronic Obstructive Pulmonary Disease (COPD), hypoxemia is associated with multiple underlying mechanisms, of which one of the most significant is ventilation-perfusion (V/Q) mismatch, which is correctable with supplemental oxygen (O2) therapy. Hypoxemia that is refractory to very high concentration of inspired O2 can be indicative of cardiac defect with shunt, e.g., a patent foramen ovale (PFO) with right-to-left (R-T-L) shunt. In hypoxemic COPD patients, the diagnosis of a PFO requires a heightened sense of clinical suspicion along with careful assessment of other underlying possibilities. Platypnea-orthodeoxia and a non-response to the hyperoxia test, while not diagnostic, increase suspicion. A correct diagnosis of interatrial bypass needs to be confirmed with transthoracic echocardiogram and contrast transesophageal echocardiography. Presently, no data are available supporting the effectiveness of PFO closure in COPD patients to relieve symptoms and correct hypoxemia. We report a case of hypoxemic COPD with platypnea-orthodeoxia syndrome due to PFO. The decision of its closure with device after echocardiographic evaluation of right ventricular function has completely corrected refractory hypoxemia with improvement of SpO2 and functional capacity. Thus, in selected COPD with refractory hypoxemia, closure of PFO should be considered as novel therapeutic target with improvement of quality of life and less likelihood of hospitalization.