Pulmonary arterial hypertension (PAH) is a potentially life-threatening complication of thalassemia. A sexagenarian with β-thalassemia intermedia presented with new-onset dyspnea and syncope. Right heart catheterization confirmed severe PAH. Her functional class IV symptoms and severely elevated mean pulmonary artery pressure prompted the initiation of continuous epoprostenol therapy. Clinical follow-up documented significant improvement in functional class, 6-minute walk distance, and right ventricular size and function as well as pulmonary arterial pressure on echocardiogram. At the patient's request, epoprostenol was down-titrated and eventually discontinued. The patient was then safely transitioned to nifedipine therapy after verification of vasoresponsiveness.