Patent foramen ovale (PFO) is diagnosed on echocardiography by saline contrast study with or without color Doppler evidence of shunting. PFO is benign except when it causes embolic events.In this report, we describe unique additional manifestations related to the diagnosis and presentation of PFO. These include demonstration of PFO during the release phase of "sigh" on the ventilator in the operating room, use of a separate venipuncture to allow preparation of blood-saline-air mixture after multiple failed saline bubble injections, resting and stress hypoxemia related to left to right shunting across a PFO in the absence of pulmonary hypertension, presentation of quadriperesis secondary to an embolic event from a PFO and development of a thrombus on the left atrial aspect of PFO in a patient with atrial fibrillation, and on the right atrial aspect of PFO in a patient who had undergone repair of a flail mitral valve. Finally, in one patient with end-stage renal disease, aortic valve endocarditis and periaortic abscess, PFO acted as a vent valve relieving right atrial pressure following development of aortoatrial fistula.PFO diagnosis can be elusive if appropriate techniques are not used during saline contrast administration. PFO can present as hypoxemia in the absence of pulmonary hypertension, can be a rare cause of quadriperesis, and can be associated with thrombus formation on either side of interatrial septum. Finally, PFO presence can be lifesaving in those with sudden increase in right atrial pressure such as with aortoatrial fistula.