This study was designed to evaluate whether the ventilatory maneuvers associated with surfactant replacement would, per se, influence oxygenation in newborn infants with severe respiratory distress syndrome. Eight patients (700 to 1400 g), all requiring mechanical ventilation with fraction of inspired oxygen >0.6, were included in the trial; four were randomized to receive surfactant, and the others served as controls. Porcine surfactant (2 ml/kg; phospholipid concentration, 100 mg/ml) was instilled via a naso-endotracheal tube at end-expiration and dispersed into the lungs during a period of standardized “sighing” mediated by the ventilator: two prolonged ventilatory cycles (10 sec each) with an inspiration/expiration ratio of 4:1, followed by a 6-min ventilation with a frequency of 60 breath/min and an inspiration/expiration ratio of 4:1. Control babies received no surfactant but were otherwise subjected to the same ventilatory maneuvers. Surfactant-treated infants showed a rapid increase in transcutaneous oxygen associated with improved lung aeration in chest x-rays; the response was transient in three babies and persistent in one. No improvement was observed in control babies. We conclude that the beneficial effect of surfactant replacement cannot be attributed to the ventilatory maneuvers associated with the instillation procedure.