In newborn rats, antenatal thyroid stimulation with thyroid-releasing hormone is associated with developmental decreases in pulmonary antioxidant enzyme activities and decreased survival rates during prolonged hyperoxic exposure, with pathologic evidence of increased O2-induced lung damage. Propylthiouracil (PTU), in addition to its antithyroid effects, reportedly has antioxidant properties. To explore possible pulmonary protective effects from both the antithyroid and antioxidant properties of PTU, we administered PTU (0.015%) in drinking water to timed-pregnant rats for the final 10 d of gestation and during lactation; control rats received untreated water. The survival rate of the PTU-treated pups when placed in more than 95% O2 at birth was consistently higher at all time periods in hyperoxia from 6 d [PTU, 81 of 81 (100%); control pups, 70 of 84 (83%); p < 0.01] to 14 d [PTU, 41 of 53 (77%); control pups = 14 of 56 (25%); p < 0.01]. Further evidence of increased tolerance to more than 95% O2 in PTU pups included a significant decrease in the incidence of microscopic intraalveolar edema, decreased lipid peroxidation (malondialdehyde), and a significant increase in lung tissue surfactant-related phospholipids compared with O2-exposed control pups. No differences were present in lung structural maturation, antioxidant enzyme activity response to hyperoxia, or lung tissue O2 radical formation in more than 95% O2. We conclude that PTU treatment has important postnatal effects that protect newborn rats against oxidant-induced lung injury and lethality during hyperoxia, which may be related to PTU inhibition of thyroid hormone production, effect on O2 metabolism, or its direct antioxidant properties.