A 68-year-old woman presented with progressive and severe effort-related dyspnea. Her history included an ischemic stroke at age 43. Routine exams were normal. Cardiopulmonary exercise testing (CPET) showed a reduction in PaO2 from 11.8 kPa to 4.8 kPa. Repeated CPET with 100 % inhaled O2 improved the drop in PaO2 marginally. Transesophageal echocardiography revealed a shunt from right to left through a patent foramen ovale (PFO). A right heart catheterization showed normal pressures and no signs of intrapulmonary shunting. The PFO was closed percutaneously and the patient's symptoms resolved almost completely. Platypnea-orthodeoxia syndrome is an uncommon disorder where the pathophysiological mechanisms include a right-to-left shunt, either intracardiac or pulmonary. The most common intracardiac shunt related to the syndrome is a PFO. Platypnea-orthodeoxia syndrome, although rare, merits our attention, since it is often easily treatable. The key finding is desaturation on standing up.