OBJECTIVE To ascertain possible mechanisms implicated in the development of transient episodes of hypoxemia (oxygen saturation < 85%) frequently observed in preterm infants undergoing mechanical ventilation, even after the acute phase of respiratory failure has passed. METHODS Tidal flow, airway and esophageal pressure, and oxygen saturation were continuously recorded in 10 infants (mean +/- SD, birth weight 733 +/- 149 gm, gestational age 25.5 +/- 2.2 weeks, age 26.3 +/- 11.9 days) who had repeated episodes of hypoxemia without any evident cause. Measurements of minute ventilation (VE) inspiratory compliance (Ci), and inspiratory resistance (Ri) were compared before and during episodes of hypoxemia. RESULTS All episodes of hypoxemia were preceded by an active exhalation that produced a mean decrease in end-expiratory lung volume of 6.4 +/- 2.8 ml/kg. The reduction in lung volume was immediately followed by a sudden decrease in tidal flow and volume, despite continuation of mechanical ventilation at the same rate and peak pressure. The resulting hypoventilation was associated with a drop in Ci to approximately one half and an increase in Ri to more than double the baseline values. Approximately 30 seconds after the beginning of hypoventilation, the arterial oxygen saturation reached a hypoxemic level (oxygen saturation < 85%)> CONCLUSIONS Most hypoxemic episodes were triggered by an expiratory effort that produced a large decrease in lung volume. This reduction in lung volume probably leads to closure of small airways and the development of intrapulmonary shunts, which would explain the rapid development of hypoxemia.