Inhaled NO (iNO) has an established role in the treatment of pulmonary hypertension (PH) in the newborn. However, costs and potential toxicity associated with iNO have generated interest in alternative inhaled selective pulmonary vasodilators such as iloprost. In a preterm lamb model of respiratory distress syndrome, we studied effects of increasing doses of iloprost followed by iNO on right ventricular pressure (RVP) and circulation including cerebral oxygenation. Fetal sheep were randomized to three doses (0.2-4 mg/kg) of iloprost (n ϭ 9) or saline (n ϭ 10), administered as 15-min inhalations with 15-min intervals after a 60-min postnatal stabilization. No differences were found in RVP, arterial PO 2 , or cardiac index according to treatment. The cerebral oxygenation, measured with near-infrared spectroscopy, deteriorated in control lambs, but not in iloprost lambs. Iloprost treatment followed by iNO resulted in a larger decrease (p ϭ 0.007) in RVP than saline treatment followed by iNO. In conclusion, iloprost stabilized cerebral oxygenation and when followed by iNO had a larger effect on RVP than iNO alone. Although species differences may be relevant, these results suggest that iloprost should be studied in newborn infants for the treatment of PH. circulation, the pulmonary vascular resistance decreases rapidly. The vascular tone in pulmonary arteries is regulated by a balance of vasoconstrictors and vasodilators. Endothelin, hypoxemia, and acidemia have strong constrictor effects on pulmonary arterioles (1). The main endogenous vasodilators are the endothelial-derived substances NO and prostacyclin, which increase endothelial cell production of cGMP and cAMP, respectively (1). When the transition is disturbed, the pulmonary arterial resistance remains elevated resulting in considerable hypoxemia and low-oxygen delivery to tissue. As arterial O 2 tension does not necessarily reflect the oxygen delivery to tissue because of low perfusion or extraction, near-infrared spectroscopy (NIRS) has been applied to monitoring tissue oxygenation (2).Inhaled NO (iNO) exerts a rapid pulmonary vasodilatation and is an established treatment of pulmonary hypertension (PH) in newborn infants (3). iNO has, however, several disadvantages, such as unpredictable and nonsustained effect, and rebound PH after withdrawal (4). The toxic NO product peroxynitrite inhibits prostacyclin synthase (5), the key enzyme of prostacyclin synthesis. Further, NO causes an increased endothelin-1 release (6). Thus, other effective agents with fewer side effects are sought for the treatment of PH in the newborn.Prostanoids have been administered in the clinical setting mainly in adults as i.v. infusions of prostacyclin, s.c. infusion of treprostinil, and inhalations of iloprost (7). I.v. prostacyclin causes severe systemic hypotension in newborns (8). Inhaled prostacyclin decreases pulmonary vascular resistance without decreasing systemic blood pressure. The prostacyclin analogue iloprost has a longer half-life (almost 30 min) than prostac...