The response of the injured lung to hyperoxia is uncertain. In the present study, we evaluated the effects of 100% oxygen exposure for 120-168 h in mechanically ventilated baboons with or without previous diffuse alveolar damage (DAD) induced by oleic acid. These two groups were compared with another group of six baboons previously studied in our laboratory in which DAD induced with oleic acid was followed by ventilation with 40% oxygen. Oleic acid infusion caused a prompt reduction in total lung capacity, static compliance, and diffusion capacity and an increase in lung tissue volume. The magnitude and course of oleic acid lung injury was similar for 4 days in animals breathing 100% or 40% O2. Animals breathing 100% O2 without previous lung injury developed significant decreases in total lung capacity, oxygenation, and diffusion capacity after 72 h of hyperoxia. By 120 h, lung function was similarly impaired in both 100% O2-breathing groups, and rapidly worsening pulmonary edema appeared radiographically between 5.5 and 7 days in all O2-exposed animals. Subsequent weaning was successful in only three animals after 100% O2 exposure. All but one animal in the 40% O2 group were easily weaned. Histologic changes between 6 and 14 days in 100% O2 animals showed a marked proliferative response, particularly of type 2 cells; no differences were found due to prior oleic acid injury. Resolution of this process occurred in a surviving animal, resulting in focal fibrotic residua at 6 weeks, similar to that observed in 40% O2 oleic acid-treated survivors. Previous lung injury due to oleic acid did not modify the response of the baboon lung to hyperoxia.