The effect of peak airway pressure (Paw) on vascular permeability and the "safety factor" against edema formation was determined in isolated blood-perfused lower lobes of dog lungs. Microvascular permeability was evaluated using the measured filtration coefficient (Kf,C), isogravimetric capillary pressure (Pc,i), and critical capillary pressure (Pcrit) for exhaustion of tissue safety factors. Airway pressure was maintained constant at -3 cmH2O except for the test period of 20 min when the lungs were ventilated at 6/min with sufficient volume to generate a peak inflation pressure ranging from 5 to 60 cmH2O. Mean Kf,C (in ml X min-1 X cmH2O X 100 g-1) were measured before and immediately after the period of peak airway pressures. Kf,C was significantly increased in all lungs where Paw exceeded 42 cmH2O, but in only two experiments at a lower Paw. Mean Pc,i was significantly reduced from control in the 45-55 and 55-65 cmH2O Paw groups, and both Pc,i and Pcrit were found to be inversely related to Kf,C measured after Paw ventilation. These data indicate that ventilation with Paw above 42 cmH2O (30.9 Torr) and in some cases lower pressures for 20 min significantly increased capillary hydraulic conductivity, reduced the effective osmotic effect of plasma proteins at the capillary wall, and reduced the total tissue safety factor against edema formation.