A 52 year old female presented for two weeks of acute onset dyspnea on exertion. She was found to be hypoxic with a room air saturation of 88%. Baseline echocardiogram was normal with the exception of aortic root dilation. Right and left heart catheterizations were performed. The coronary arteries were normal in original and without disease. The right heart catheterization demonstrated normal pulmonary pressures and "no evidence of intra-cardiac shunt". Repeat echocardiogram was performed with agitated saline contrast and revealed a small amount of right to left shunting across the intra-atrial septum with cough while supine and significant right to left shunting while upright; these findings were consistent with the presence of a patent foramen ovale (PFO) and platypnea-orthodeoxia syndrome. The patient underwent percutaneous closure of her PFO with an Amplatzer device, and exhibited rapid resolution of her symptoms and hypoxia. She is off oxygen and has returned to work as a nurse practitioner. The case highlights the importance of clinical vigilance and consideration of this syndrome in the differential diagnosis of unexplained hypoxia. Our patient had a dramatic and positive outcome: complete alleviation of dyspnea and oxygen dependence after PFO closure.