This study was designed to test the hypothesis that nitric oxide inhalation increases systemic arterial blood oxygen tension of prematurely delivered infants. Nitric oxide was administered to twenty premature infants (28.0± 0.8 weeks gestational age) who had previously been treated for respiratory distress syndrome with exogenous surfactant. Between 24 hours and 168 hours after delivery, the infants were randomized to receive either 5 ppm or 20 ppm of nitric oxide. The nitric oxide administration period for each infant lasted 15 minutes and was preceded by and followed by a 15 minute control period. For each infant, the ventilator settings remained unchanged throughout the study periods. All outcome variables were evaluated using two way repeated measures analysis of variance; p values less than 0.05 were considered significant. Nitric oxide inhalation caused significant increases in: arterial blood oxygen tension (from 74.4 ± 5.6 mmHg to 113.7± 8.5 mmHg), directly measured arterial oxyhemoglobin saturation (from 96.0 ± 0.0% to 98.4 ± 0.0%), and transcutaneously measured arterial oxyhemoglobin saturation (from 93.2 ± 0.0% to 97.6 ± 0.0%). No differences between the effects of the two nitric oxide concentrations were detected, nor were residual effects detected fifteen minutes after stopping either dose of nitric oxide. In conclusion, inhalation of both 5 and 20 ppm nitric oxide causes increases in the blood oxygen levels of premature infants with respiratory distress syndrome. We speculate that nitric oxide inhalation may be a useful adjunctive therapy for these patients. We recommend using nitric oxide concentrations less than 20 ppm in future related clinical trials.