Objectives To study the individual and combined effects of surfactant inactivation and mechanical ventilation on pulmonary microvascular permeability and lung compliance. Design Prospective, controlled trial. An isolated, perfused, lung model of surfactant inactivation and mechanical ventilation at 15,30, and 45 cm H2O peak inspiratory pressure was developed in young (4 to 6 wks) New Zealand white rabbits. Setting Laboratory of a university-affiliated medical school. Measurements and Main Results Isolated, perfused lungs were prepared for measurement of the capillary filtration coefficient before and after one of four interventions: instillation of dioctyl succinate, a surfactant inactivator, without ventilation (group 1); ventilation without dioctyl succinate at 15, 30, or 45 cm H2O peak inspiratory pressure (group 2); ventilation after dioctyl succinate pretreatment at 15,30, or 45 cm H2O peak inspiratory pressure (group 3); and control lungs without dioctyl succinate or ventilation (group 4). A significant increase in the capillary filtration coefficient was noted after dioctyl succinate treatment alone, after ventilation alone at 45 cm H2O peak inspiratory pressure, and after dioctyl succinate plus ventilation at 15,30, and 45 cm H2O peak inspiratory pressure. Dioctyl succinate plus ventilation produced a significantly greater increase in the capillary filtration coefficient than ventilation alone at 15 and 45 cm H2O peak inspiratory pressure. Conclusions These data suggest that ventilation after surfactant inactivation is more injurious to the pulmonary microvasculature than ventilation alone, and that generalized lung over-distention is not the primary mechanism for microvascular injury in the diseased, noncompliant lung. The increases seen in the capillary filtration coefficient in postventilated surfactant inactivated lungs, even at low-ventilation pressures, suggest that low peak inspiratory pressures do not overdistend the dioctyl succinate-treated lung. (Crit Care Med 1992; 20:635–640)