We proposed that hypoxic-ischemic injury suffered on postnatal day 1 (P1) in the newborn rat would yield significant and reproducible brain injury simulating that seen in a midgestation human brain. The P1 pup was subjected to ipsilateral common carotid ligation followed by 3.5 h of 6% O2 and demonstrated consistent histological changes in the ipsilateral hemisphere. At P2 neuronal loss and edema were pronounced in cortex and caudate; edema subsequently declined by P3. Astrocytic and microglial reactivity were seen as early as 24 h after injury, and by P10 both were extensive in damaged areas. There was marked loss of white matter on the affected side. We have demonstrated a reproducible model of hypoxic-ischemic injury to the very immature brain that can be used to elucidate mechanisms of neuronal loss and periventricular leukomalacia.