Three patients presented to our intensive care unit over a 3-yr period with profound hypoxia resulting from acute right-to-left inter-atrial shunt (RLIAS). Patient 1 was a 67-yr-old male with an atrial septal defect who became hypoxic and developed the rare sign of platypnoea following elective repair of an abdominal aortic aneurysm (breathlessness made worse when upright and relieved by lying flat). Patient 2 was a 38-yr-old female who developed platypnoea and hypoxia secondary to a patent foramen ovale (PFO) and pericardial effusion. Patient 3 was a 46-yr-old male with a PFO who developed hypoxia without platypnoea because of multiple pulmonary emboli following right hemicolectomy. These case reports illustrate the need to consider RLIAS as a cause of hypoxia of sudden onset. Early use of bubble contrast echocardiography is indicated.