Introduction <p>Neonatal hypoxia ischemia (HI) causes injury to the blood brain barrier (BBB), which in turn is associated with widespread cell loss. Cell therapies are currently being investigated for use in perinatal neuroprotection and umbilical cord blood (UCB) endothelial progenitor cells (EPCs; CD133+) have been previously shown to reduce gross neuropathology associated with HI; however, no study has investigated the effect of EPC treatment on the vulnerable BBB. Therefore, in this study, we investigated the effect of EPC treatment on BBB integrity in a neonatal rat model of HI.</p> Methods <p>HI brain injury was induced in postnatal day (PND) 7 rat pups via permanent ligation of the left carotid artery, followed by a 180-minute hypoxic challenge at 8% O₂. At 24&#xa0;h post-insult, 2 × 10⁵ EPCs were administered via intraperitoneal injection. At 7 days post-HI, brains and choroid plexuses were collected for immunohistochemistry or molecular analyses.</p> Results <p>Neonatal HI resulted in neuropathology, with a significant increase in left hemisphere tissue loss. This was associated with microglial activation, astrogliosis and increased expression of Aquaporin 4 in the somatosensory cortex, and EPC administration significantly reduced these outcomes. Assessment of the BBB revealed GLUT1 and claudin-5 expression were significantly increased in HI animals compared to sham, and treatment with EPCs reduced these to sham control levels.</p> Conclusion <p>EPCs are a promising treatment option for neonatal HI as they modulate BBB changes. However, further studies are needed to understand early effects of EPC treatment and how EPC therapy modulates BBB dysfunction post HI brain injury.</p> Graphical Abstract <p></p>