It has been previously shown that prophylactic, intravenous dexamethasone (DEX) and intratracheal recombinant human Cu/Zn superoxide dismutase (SOD) ameliorate lung injury in newborn piglets treated with 48 hr of hyperoxia and mechanical ventilation. DEX has many pharmacologic effects, including the possible induction of antioxidant enzyme systems. To investigate whether the effects of DEX are mediated by an increase in endogenous antioxidant enzyme activity, 5 groups of term newborn piglets were studied: Group 1 piglets were ventilated with room air for 48 hr; Group 2 animals were ventilated with 100% O2 for 48 hr; Group 3 animals were ventilated with room air for 48 hr and received DEX (0.7 mg/kg) every 12 h; Group 4 were ventilated with 100% O2 for 48 hr and also received DEX; Group 5 animals were no ventilated and were sacrificed at time 0. At the conclusion of the studies, bronchoalveolar lavage (BAL) was performed and the lungs were removed and homogenized. Lung tissue and BAL were analyzed for SOD, catalase, GPX activities, and total protein concentration. No significant differences in any of these assays were seen in either lung tissue or BAL in the 5 groups. These observations indicate that 48 hr of hyperoxia, mechanical ventilation, or dexamethasone treatment does not induce activity of SOD, catalase, or glutathione peroxidase (GPX) in the lungs of newborn piglets. Thus postnatal DEX appears to minimize neonatal lung injury by mechanisms that are independent of these enzymes.