Intratracheal administration of surfactant and inhaled nitric oxide (INO) have had variable effects in clinical trials on patients with acute respiratory distress syndrome (ARDS). We hypothesized that combined treatment with exogenous surfactant and INO may have effects in experimental ARDS. After intravenous infusion of oleic acid in adult rabbits and 4-6 h of ventilation, there was more than a 40% reduction in both dynamic compliance (Cdyn) of the respiratory system and functional residual capacity (FRC), a 50% increment of respiratory resistance (Rrs), a 70% reduction in PaO2 /FIO2, and an increase in intrapulmonary shunting (Q S/Q T) from 4.4 to 33.5%. The animals were then allocated to groups receiving (1) neither surfactant nor INO (control), (2) 100 mg/kg of surfactant (S) administered intratracheally, (3) 20 ppm INO (NO), or (4) 100 mg/kg of surfactant and 20 ppm INO (SNO), and subsequently ventilated for 6 h. After the period of ventilation, the animal lungs were used for analysis of disaturated phosphatidylcholine (DSPC) and total proteins (TP) in bronchoalveolar lavage fluid (BALF), and for determination of alveolar volume density (VV). The animals in the control group had the lowest survival rate, and no improvement in lung mechanics and blood oxygenation, whereas those in the S group had a modest but statistically significant improvement in Cdyn, Rrs, PaO2 and FRC, reduced Q S/Q T, lowered minimum surface tension (gammamin) of BALF, and increased DSPC/ TP and alveolar VV. The NO group had increased PaO2 and reduced Q S/Q T. The SNO group showed improved Cdyn, Rrs, FRC, DSPC/TP, alveolar VV, and gammamin of BALF comparable to the S group, but there was a further increase in survival rate and PaO2, and additional reduction in Q S/Q T and TP in BALF. These results indicate that, in this animal model of ARDS, a combination of surfactant therapy and INO is more effective than either treatment alone.