Twenty term/near term neonates with hypoxemic respiratory failure and oxygenation index >/=20 were enrolled in a Phase I/II feasibility, safety and dose escalation study of inhaled PGE(1) (IPGE(1)). Incremental doses of IPGE(1), delivered by a jet nebulizer over a 2-h period, followed by weaning over 1 h, were given to 13 patients before receiving inhaled nitric oxide (INO) (Group I), and to seven patients, who failed to respond to INO (Group II). Response was defined as an increase in P(a)O(2) of either >/= 25 (full) or 10-25 (partial) torr. Exit criteria included an acute deterioration in oxygenation status, a persistent oxygenation index above 35 in Group I, or the availability of extracorporeal membrane oxygenation (ECMO) in Group II. The mean (SD) increase in P(a)O(2) at the end of IPGE(1) administration was 63 (62.3) in Group I (p = 0.024), and 40 (62.1) in Group II (p > 0.05). In Group I, 8 of 13 neonates had a full response, but 4 deteriorated following discontinuation of IPGE(1). Of these four, two responded to INO and two were placed on ECMO. Five patients deteriorated before or during IPGE(1,) and none of them responded to INO. In Group II, three of seven patients had a full response to IPGE(1). One patient with a partial response and all patients exiting before or during IPGE(1) administration were placed on ECMO. The results of our study indicate that IPGE(1) may be a safe, selective pulmonary vasodilator in neonatal hypoxemic respiratory failure.