Preexposure of adult rats to ozone (0.8 +/- 0.1 ppm for 7 days) has been found to produce a marked degree of tolerance to hyperoxia (greater than 95% O2). The survival of O3-preexposed rats in hyperoxia for 168 h was 28 of 32 (88%) compared with a rate of 2 of 18 (11%) for nonpreexposed rats. Total lung superoxide dismutase (SOD), glutathione peroxidase (GP), glucose 6-phosphate dehydrogenase (G6-PD), and catalase (CAT) activities were all significantly increased after O3 preexposure and after the subsequent hyperoxic challenge. Probable mechanisms accounting for the markedly improved survival in hyperoxia after O3 preexposure include both increased lung antioxidant enzyme and repair of structural damage by proliferation of alveolar lining cells. The demonstration of cross-tolerance between the atmospheric oxidants O3 and O2 suggests that there are similarities in the lung's adaptation to both oxidants.