We previously demonstrated that inhalation of high concentrations of nitric oxide (iNO) and oxygen for 48 hr causes significant lung injury in newborn piglets. To determine if these effects persist at lower concentrations, groups of newborn piglets were mechanically ventilated for 48 hr with (study 1) constant O2 (90-100%) and decreasing iNO (100-2 ppm) or (study 2) constant iNO (50 ppm) and decreasing O2 (95-30%). Bronchoalveolar lavage (BAL) fluid was assayed for surfactant function, and markers of lung inflammation and physiologic parameters were monitored. Neutrophil chemotactic activity (NCA), % neutrophils, and total protein (TP) concentrations decreased significantly in BAL fluid of study 1 piglets as iNO was reduced and inhaled oxygen fraction remained constant, indicating less pulmonary injury at low iNO levels. Low-dose iNO (2 ppm) did not have antiinflammatory effects, However, surfactant function was minimally affected by lowering iNO, and was abnormal in all groups. In contrast, in study 2, pulmonary inflammation and injury were lower when O2 was decreased to 70% or less, with iNO constant at 50 ppm. Surfactant function normalized and oxygenation improved in study 2 piglets when the inhaled oxygen fraction was decreased and iNO remained constant. These data suggest that iNO- and O2-induced lung injury may be minimized by weaning O2 or iNO, although better physiologic function may be obtained when iNO concentrations are constant and O2 is reduced. This has important implications in the clinical management of critically ill newborns treated with O2 and iNO for pulmonary disorders. © 2002 Wiley-Liss, Inc.