We used a small animal respirator to ventilate normal, anesthetized rats with room air at peak inspiratory pressures of 14, 30, or 45 cm H₂O and no added end-expiratory pressures (intermittent positive pressure breathing [IPPB] 14/0, high inspiratory positive pressure breathing [HIPPB] 30/0, HIPPB 45/0). Other rats were ventilated with the same high inspiratory pressures but with an added end-expiratory pressure of 10 cm H₂O (positive end-expiratory pressure [PEEP] 30/10, PEEP 45/10). Control rats that were not ventilated and the IPPB 14/0 group showed no pathologic lung changes. The HIPPB 30/0 and PEEP 30/10 groups had perivascular edema but no alveolar edema. The HIPPB 45/0 animals had alveolar and perivascular edema, severe hypoxemia, and decreased dynamic compliance and died within one hour. In contrast, the PEEP 45/10 animals had no alveolar edema and survived. We postulate that interstitial perivascular edema develops from ventilation with high inflating pressures by mechanisms of lung interdependence, which decrease the pressure in the perivascular tissues. Alveolar edema induced by HIPPB 45/0 may result from surfactant depletion because of large excursions of alveolar surface area and a low surface tension at end-expiration.