Pulmonary oxygen toxicity is believed to play a prominent role in the lung injury that leads to the development of bronchopulmonary dysplasia (BPD). To determine whether human recombinant erythropoietin (rhEPO) treatment reduces the risk of developing BPD, we investigated the effect of rhEPO treatment on the histopathologic changes seen in hyperoxia-induced lung injury of BPD. Twenty-five rat pups were divided into four groups: air-exposed control group (n ϭ 5), hyperoxia-exposed placebo group (n ϭ 7), hyperoxia-exposed rhEPO-treated group (n ϭ 6), and air-exposed rhEPO-treated group (n ϭ 7). Measurement of alveolar surface area, quantification of secondary crest formation, microvessel count, evaluation of alveolar septal fibrosis, and smooth muscle actin immunostaining were performed to assess hyperoxia-induced changes in lung morphology. Treatment of hyperoxia-exposed animals with rhEPO resulted in a significant increase in the mean alveolar area, number of secondary crests formed, and the microvessel count in comparison with hyperoxia-exposed placebo-treated animals. There was significantly less fibrosis in rhEPO-treated animals. However, treatment of hyperoxia-exposed animals with rhEPO did not result in a significant change in smooth muscle content compared with hyperoxia-exposed placebo treated animals. Our results suggest treatment with rhEPO during hyperoxia exposure is associated with improved alveolar structure, enhanced vascularity, and decreased fibrosis. Therefore, we conclude that treatment of preterm infants with EPO might reduce the risk of developing BPD. Despite the improvements in preventing acute respiratory disease in preterm infants, the incidence of BPD remains largely unchanged. The pathophysiology of BPD has been extensively studied for several decades, and pulmonary oxygen toxicity is believed to play a prominent role in the lung injury process that leads to the development of BPD (1). Histopathologic characteristics of the lung injury in BPD are lack of increased complexity (a decrease in alveolarization), abnormal capillary morphology, and an interstitium with variable cellularity/fibroproliferation (2).The treatment goals of BPD focus on minimizing ongoing injury, reducing inflammation, maintaining adequate oxygenation, and facilitating lung growth. A number of groups have used antioxidants to prevent BPD without any significant benefit (3). Corticosteroids facilitate extubation and decrease neonatal respiratory support and oxygen exposure. However, these short-term benefits are achieved at the expense of serious neonatal complications such as poor brain and somatic growth, and substantially worse neuromotor and developmental outcomes in early childhood (4). Therefore, investigating the effectiveness of new strategies in the treatment of BPD is of great interest.EPO is a 30.4-kD glycoprotein that regulates the rate of red blood cell production, through binding to its specific cell surface receptors. It has been used for many years to treat anemia of prematurity (5,6). In addition, in...