Platypnea-orthodeoxia is a rare and poorly understood syndrome of orthostatic accentuation of a right-to-left shunt, usually across a patent foramen ovale. The syndrome is most commonly recognized in patients with a history of a major pulmonary disorder such as pneumonectomy, recurrent pulmonary emboli, or chronic lung disease. Pulmonary artery pressures are typically normal. The physiologic mechanism is unknown. We recommend that initial assessment consist of measurement of blood gases with the patient in the supine and upright positions. Orthostatic desaturation should prompt further investigation. A definitive diagnosis can most easily be obtained by tilt-table two-dimensional echocardiography with peripheral venous contrast medium. The shunt can be localized at the atrial level and directly visualized and semiquantitated. The decision about surgical closure of the patent foramen ovale is based on the degree of clinical disability. Because a significant shunt is manifest only in the upright position, astute clinical suspicion is of paramount importance for proper diagnosis. Increased awareness of this syndrome and ease of echocardiographic diagnosis will facilitate recognition of this potentially treatable cause of orthostatic hypoxia.