This study tested the hypothesis that inhaled nitric oxide (NO) and combined NO and hyperoxia will result in less pulmonary dysfunction and delay onset of respiratory signs compared with hyperoxia-exposed newborn guinea pigs (GPs). GPs were exposed to room air (n = 14), 95% O(2) (n = 36), 20 parts per million (ppm) NO (n = 14), or combined 20 ppm NO and 95% O(2) (NO/O(2), n = 13) for up to 5 days. Data evaluated included latency interval for onset of respiratory distress, pressure volume curves, lung histology, and bronchoalveolar lavage (BAL) polymorphonuclear cells (PMNs), proteolytic activity, and total protein. NO-exposed GPs did not develop respiratory distress and had no evidence of pulmonary dysfunction. O(2)-exposed GPs developed respiratory distress after 1-5 days (median 4.0) vs. 3-5 days (median 5.0) for NO/O(2) exposure (P < 0.05). BAL from O(2)-exposed GPs showed increased PMNs compared with NO/O(2)-exposed GPs. O(2)- and NO/O(2)-exposed GPs had comparable reduced lung volumes, lung histology, and increased BAL proteinase activity and total protein. In summary 1) O(2) exposure resulted in multiple measures of pulmonary dysfunction in newborn GPs, 2) 5-day exposure to NO produced no noticeable respiratory effects and pulmonary dysfunction, and 3) short-term exposure (</=5 days) to NO/O(2) delayed onset of respiratory distress and neither exacerbated nor attenuated pulmonary dysfunction compared with O(2) exposure alone.