<b><i>Introduction:</i></b> Continuous improvements in perinatal care have allowed the survival of increasingly more prematurely born infants. The establishment of respiration in an extremely immature yet still developing lung results in chronic lung injury with significant mortality and morbidity. We experimentally evaluated a novel medical strategy to prevent hyperoxia-induced lung injury by prenatal rosiglitazone. <b><i>Materials and Methods:</i></b> Pregnant rabbits were injected with saline or rosiglitazone (3 mg/kg) 48 and 24 h prior to preterm delivery at 28 days of gestation (term = 31 days). The pups were held in normoxia (21% O₂) or hyperoxia (>95% O₂), and assessment was done at three different time points (1 h, 24 h and 7 days). <b><i>Results:</i></b> The administration of rosiglitazone resulted in a significant decrease in tissue damping (resistance) on day 7. Furthermore, significantly increased expression of vascular endothelial growth factor, fetal liver kinase 1 and surfactant protein B immediately after delivery was noted by immunohistochemistery. On day 7, there was a more mature lung parenchymal architecture in rosiglitazone-exposed pups. <b><i>Discussion:</i></b> In a preterm rabbit model, prenatal maternal administration of rosiglitazone attenuates neonatal hyperoxic lung injury and results in a more mature pulmonary parenchyma.