Nerve growth factor (NGF) has been shown to protect specific neurons that express its signaling receptor, trkA, from a variety of insults. There are some data, in particular in the developing brain, indicating that NGF has neuroprotective actions that extend beyond cells expressing trkA. In this study, we asked whether NGF would protect against brain injury in a neonatal model of hypoxia-ischemia. Postnatal day (PD) 7 rat pups received a right carotid ligation and were then exposed to hypoxic conditions. Prior to carotid ligation and 48 hours later, pups received an intracerebroventricular injection of NGF or denatured NGF dissolved in vehicle or vehicle alone. Brains were then assessed at PD21. In vehicle- and denatured NGF-treated animals, there was significant damage (30-40% volume loss) to both the striatum and cortex ipsilateral to the carotid ligation. In contrast, little damage (10% volume loss) was observed in most NGF-treated animals. NGF injection studies revealed that NGF stimulated tyrosine phosphorylation of trkA in multiple brain regions. These results show that NGF appears globally neuroprotective to the developing brain in a neonatal model of hypoxia- ischemia and that there may be novel mechanisms in vivo through which NGF exerts its protective actions.