Platypnea-Orthodeoxia syndrome (POS) is a rare clinical syndrome characterized by shortness of breath in the upright position that is relieved with supine positioning. We present a rare case of persistent left superior vena cava (PLSVC) draining into the left atrium causing a right-to-left shunt and subsequent POS. A 30-year-old female with a past medical history of hypertrophic cardiomyopathy, congenital Long QT syndrome and a left-sided dual chamber implantable cardioverter-defibrillator (ICD) presented with dyspnea and lightheadedness. Prior to presentation, the patient underwent a leftsided ICD extraction due to ICD lead infection and re-implantation from the right side through the cephalic vein. After further investigation, it was concluded that the PLSVC resulted in a physiological right-to-left shunting causing POS, with resolution of her symptoms after surgical ligation. To our knowledge, this is the first case report of PLSVC presenting with POS without anatomical intracardiac shunts following iatrogenic right superior vena cava (RSVC) obstruction.