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Abstract Objectives This study reviewed a series of patients treated with transcatheter closure of septal defect to treat platypnea-orthodeoxia syndrome, with specific attention to septal characteristics and device choice. Background Platypnea–orthodeoxia syndrome is an uncommon condition characterized by positional dyspnea and hypoxemia due to intracardiac right-to-left shunting through a patent foramen ovale (PFO), an atrial septal defect, or pulmonary arteriovenous malformations. Percutaneous closure of such defects is the treatment of choice. Methods In this single-center series, 52 patients were treated with percutaneous closure of an interatrial communication after presentation between January 1997 and July 2015. Septal morphology, clinical, procedural, and outcomes data were analyzed. Results All patients had a PFO; however, nearly one-quarter required a non-PFO device (11 Amplatzer Septal Occluder and 1 post-infarct muscular VSD), as opposed to a dedicated PFO device to achieve shunt occlusion. These patients were characterized by an aneurysmal septum, shorter primum septum overlap with the secundum septum, and greater septal angulation from the midline. After closure, all demonstrated acute improvements in oxygen saturation (pre-procedure: 81 ± 8%; post-procedure: 95.1 ± 0.5% on room air). Each patient was treated with a single device and no one required re-intervention. Conclusions Patients presenting with platypnea–orthodeoxia syndrome can be treated successfully with a percutaneous intervention often requiring a variety of devices. Those requiring a non-PFO–type device had a greater prevalence of an aneurysmal septum, shorter primum septal overlap with the secundum septum, and greater septal angulation with the midline.