In preterm infants with respiratory distress syndrome, surfactant administration followed by immediate extubation to spontaneous breathing with nasal continuous positive airway pressure reduces the need for mechanical ventilation. With this treatment approach, repeated doses of surfactant are rarely indicated. We used a rabbit model to test the hypothesis that exogenous surfactant therapy followed by spontaneous breathing results in a more sustained initial treatment response compared with treatment followed by mechanical ventilation. Preterm rabbits (gestational age 28.5 d) were treated with pharyngeal deposition of 200 mg/kg radiolabeled surfactant (14C-Curosurf) and randomized to 4 h of spontaneous breathing or mechanical ventilation or to a control group, killed immediately after surfactant administration. With pharyngeal deposition, 46 +/- 10% (mean +/- SEM) of the administered surfactant reached the lungs. The dynamic lung-thorax compliance was higher in spontaneously breathing compared with mechanically ventilated animals (median, 9.9 and 0.75 ml x cm H2O(-1) x kg(-1), respectively; p < 0.05). The relative distribution of 14C-Curosurf in bronchoalveolar lavage fluid and homogenized lung tissue showed a higher degree of tissue association in the spontaneously breathing animals [53 +/- 4 versus 26 +/- 3% (mean +/- SEM)] than in mechanically ventilated animals (p < 0.01), the latter figure being very similar to that of the control group (25 +/- 5%). There was a higher degree of lipid peroxidation and fewer microbubbles in bronchoalveolar lavage fluid from mechanically ventilated animals. We conclude that the initial lung tissue association of exogenous surfactant is impaired by mechanical ventilation. This is associated with a reduction of dynamic compliance and evidence of increased surfactant inactivation.