Transposition of the great arteries (TGA) in the newborn combined with persistent pulmonary hypertension was reported previously to occur in 3-12 % of full-term neonates with TGA. Right-to-left shunting at the ductal level causes severe hypoxemia despite prostaglandin infusion and balloon atrial septostomy. Although the introduction of inhaled nitric oxide (iNO) has improved the prognosis, this condition still is associated with high preoperative mortality. This report describes the case of a newborn with TGA and persistent pulmonary hypertension, which was managed successfully with oral sildenafil, iNO, and inhaled iloprost during life-threatening acute pulmonary hypertension, thus preventing the use of extracorporeal membrane oxygenation.