BACKGROUND: The lungs of very preterm human babies display deficits in alveolarization and vascularization as a result of the clinical use of high oxygen treatment (leading to hyperoxia) required to decrease the risk of mortality. Detailed analyses of the persistence of the respiratory deficits following this treatment and means to restore a normal state have not been investigated in full detail. In this study, high oxygen administration to neonatal mouse lungs was established as a proxy to hyperoxia in human preterm infant lungs, to better characterize the associated deficits and thus provide a means to assist in the development of treatments in the future. METHODS: Ninety percent oxygen was administered to newborn mice for four consecutive days. The effects of this treatment upon alveolarization and vascularization were investigated by morphometric, histochemical, immunohistochemical and protein analyses at day five (D5), D28 and D56 postpartum. RESULTS: Relative to control untreated lungs, septation of hyperoxic lungs was significantly reduced and airspaces were significantly enlarged at all stages examined. Furthermore, compared to controls, the number of secondary septa per tissue area was significantly reduced at D5, significantly increased at D28 and then the same as controls at D56. Analysis of vascularization parameters indicated a reduction in mature blood vessel number and the amount of Pecam1 at D5. Both of these parameters returned to control levels by D28. CONCLUSIONS: This study suggests that administration of high oxygen to underdeveloped lungs has a transient reductive effect on secondary septal number and pulmonary vascularization and a significant long-term reduction in alveolarization persisting into adulthood. This model can be used for future research of premature lung disease therapies in humans, addressing these short term septal and vascular and long term alveolar deficits, specifically relating to injury by hyperoxia.