Pulmonary arterial hypertension (PAH) is a life-threatening disease of the pulmonary arterioles, which, in the absence of effective therapy, progresses rapidly to right heart failure and death. Opening of a patent foramen ovale (PFO) is common in patients with severe pulmonary hypertension (PH), resulting in resistive hypoxemia. We report the case of a 40-year-old woman with idiopathic pulmonary hypertension (iPAH) in New York Heart Association (NYHA) class III to IV, who was admitted in the intensive care unit with hemodynamic compromise and severe hypoxemia due to right-to-left shunt throughout a PFO. Combination therapy initially with inhaled iloprost and sildenafil, and then addition of an endothelin A receptor-selective antagonist (sitaxsentan), resulted in impressive improvement in oxygenation with reversal of the right-to-left shunt and marked improvement in functional class of the patient.