Neonatal and adult animals of five species were exposed to 95+% O2. Survival time and changes in lung antioxidant enzyme activity (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GP)) in response to hyperoxia were determined. Adult animals succumbed to O2 lung toxicity in 3--5 days. Neonatal rats, mice and rabbits showed minimal lung changes after 7 days of hyperoxic exposure and these same neonatal animals showed rapid and significant increases in lung antioxidant enzyme activities. In contrast, neonatal guinea pigs and hamsters had no lung antioxidant enzyme response to hyperoxia and these neonates died in 95+% O2 as readily as their respective parent animals. Results from an in vitro hyperoxic exposure system suggest that the lack of enzymic response of the guinea pig (and hamster) neonates to O2 challenge is due to an inherent pulmonary biochemical unresponsiveness rather than to a deficiency of a necessary “serum factor.” The results of this species and age study support the important role of the lung antioxidant enzyme defense system in protection of the lung from O2-induced injury.