We explored the pulmonary effects of continuous mechanical ventilation (MV) at a peak inspiratory pressure of 50 cm H2O in healthy, paralyzed, and anesthetized adult sheep during a period of 48 h. The 9 control sheep (Group A) were ventilated with 40% oxygen at a tidal volume of about 10 ml/kg and a peak inspiratory pressure of 15 to 20 cm H2O. All these animals remained stable throughout the 48 h of MV with no change in lung function. The 7 sheep in Group B were ventilated with 40% oxygen using a pressure-controlled ventilator at 50 cm H2O peak inspiratory pressure, at a VT of 50 to 70 ml/kg. All sheep in Group B developed severe respiratory failure and died or were killed within 2 to 35 h, and showed parenchymal consolidation at autopsy. The 9 sheep in Group C were ventilated as in Group B, except that 3.8% CO2 was added to the inspired gases: the Group C animals deteriorated more slowly, with little change in PaO2 but with a severely reduced FRC, VT, total static lung compliance, and grossly abnormal lungs at autopsy. We conclude that in this model, mechanical ventilation at peak airway pressure of 50 cm H2O will lead to progressive impairment in pulmonary mechanics, lung function, acute respiratory failure, and alveolar cellular dysfunction, as demonstrated by highly abnormal minimal surface tension values of saline lung lavage fluid in both study groups.