Inhaled nitric oxide (iNO) has been shown effective in the treatment of hypoxic term newborn infants; its use in premature infants has been limited because of concern that, through its effect on platelet function, iNO might increase the incidence of intraventricular hemorrhage (IVH). As a pilot study, premature newborn infants with RDS whose oxygenation indices exceeded birthweight-specific criteria were randomly assigned to treatment with (iNO group) or without (prospective control group) iNO. Within each group, premature infants were further randomized to receive either conventional ventilation or high-frequency oscillatory ventilation. The concentration of iNO was begun at 20ppm and weaned to 5ppm over 24-48 hours. Premature infants assigned to the iNO group were maintained on 5ppm for seven days. If the infant's pulmonary condition deteriorated when iNO was stopped, the iNO was re-started and weaned over several days. Routine cranial ultrasonography was performed and interpreted by an attending pediatric radiologist unaware of the treatment group assignment. The incidence of significant IVH (Papille Grade III and IV) and periventricular leukomalacia (PVL) in the iNO (n=11) and prospective control (n=12) groups were compared. In addition, these two groups were compared to 508 premature infants, who did not receive iNO, treated in the same neonatal ICU between 1991and 1995 (historical control group) using Chi square analysis. The three groups were of similar birthweight and gestational age: iNO: 905±99g (±SEM) and 26.7±0.8 weeks; prospective control: 939±83g and 27.5±0.6 weeks; historical control: 978±10g and 28.2 weeks. No statistical differences in the incidence of Grade III or IV IVH were detected: iNO 9.1%; prospective control 16.7%; historical control 15.5% (p=0.88). No PVL was detected in either the iNO or prospective control group. Other hemorrhagic complications, such as pulmonary hemorrhage and hematuria, were not increased in the iNO group. Methemoglobin concentration was <5% in all premature infants throughout the study. These preliminary data demonstrate that iNO does not increase significant, ultrasonographically detectable IVH or PVL in premature infants. As used in this protocol, iNO appears safe. This important finding serves to justify continued study of iNO to confirm its safety and determine its effectiveness in the treatment of premature infants with RDS.