Platypnea-orthodeoxia is a rare pattern of dyspnea with arterial hypoxemia. Platypnea is defined as dyspnea induced by upright posture, and it is relieved by the recumbent position. Orthodeoxia refers to arterial desaturation resulting from assuming an erect or upright position. The case reported involves a 59-year-old man with profound, unexplained dyspnea despite extensive investigation performed at the referring institution. The difficulty in diagnosis persisted until it was recognized that the investigations, in having been performed under "standard" (supine) conditions, were insufficient and therefore misleading. Despite normal supine intracardiac pressures, a patent foramen ovale was shown to give rise to a large orthostatic intracardiac shunt, demonstrated by means of an echocardiogram performed with the patient supine and upright. Surgical closure of the foramen was followed by dramatic clinical improvement. Among dyspneic patients, discernment of a pattern of platypnea and orthodeoxia is key to effective evaluation.