Platypnea-orthodeoxia (P-O) syndrome is an underdiagnosed condition characterized by dyspnea and deoxygenation accompanying a change from a recumbent to an upright position. It is caused by increased right-to-left shunting of blood on assuming an upright position. The diagnosis of this shunt is often challenging. A case where a diagnosis was missed despite performing a tilt transesophageal echocardiogram with bubble study and a technetium labeled macroaggregated albumin scan is presented. However, a large patent foramen ovale (PFO) was found on autopsy. A brief overview of the diagnostic workup and management of this condition along with methods to increase the sensitivity of diagnostic tests is discussed.