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Treatment of preterm human infants with high oxygen can result in disrupted lung alveolar and vascular development. Local or systemic administration of endothelial progenitor cells (EPCs) is reported to remedy such disruption in animal models. In this study, the effects of both fresh (enriched for KDR) and cultured bone marrow (BM)‐derived cell populations with EPC characteristics were examined following hyperoxia in neonatal mouse lungs. Intraperitoneal injection of fresh EPCs into five‐day‐old mice treated with 90% oxygen resulted in full recovery of hyperoxia‐induced alveolar disruption by 56 days of age. Partial recovery in septal number following hyperoxia was observed following injection of short‐term cultured EPCs, yet aberrant tissue growths appeared following injection of long‐term cultured cells. Fresh and long‐term cultured cells had no impact on blood vessel development. Short‐term cultured cells increased blood vessel number in normoxic and hyperoxic mice by 28 days but had no impact on day 56. Injection of fresh EPCs into normoxic mice significantly reduced alveolarization compared with phosphate buffered saline‐injected normoxic controls. These results indicate that fresh BM EPCs have a higher and safer corrective profile in a hyperoxia‐induced lung injury model compared with cultured BM EPCs but may be detrimental to the normoxic lung. The appearance of aberrant tissue growths and other side effects following injection of cultured EPCs warrants further investigation. S tem  C ells  T ranslational  M edicine   2017;6:2094–2105

Fresh Noncultured Endothelial Progenitor Cells Improve Neonatal Lung Hyperoxia‐Induced Alveolar Injury