Our objective was to establish a nonhuman primate model of perinatal asphyxia appropriate for preclinical evaluation of neuroprotective treatment strategies under conditions that closely resemble human neonatal emergencies, and to begin testing the safety and efficacy of erythropoietin neuroprotective treatment. Prior to delivery by hysterotomy, the umbilical cords of near term Macaca nemestrina (n = 8) were clamped for times ranging between 12 and 15 min. Animals received erythropoietin (5,000 U/kg/dose x 2 i.v., n = 3), or vehicle (n = 5) after resuscitation. We assessed physiologic parameters, continuous electroencephalogram, magnetic resonance imaging/spectroscopy, safety parameters and behavior. Animals were euthanized at 4 months of age. Mean birth weight was 507 +/- 62 g. Initial arterial pH ranged from 6.75 to 7.12, with base deficits of 17-25 mEq. Animals were flaccid at birth, with attenuated electroencephalograms, and seizures occurred in 3 of 8 animals. We demonstrated magnetic resonance imaging/spectroscopy changes consistent with hypoxia (elevated lactate levels were present in some animals), significant motor and behavioral abnormalities (particularly with 15 min of cord clamping), and evidence of gliosis at the time of death. We have established a reproducible model of moderate to severe perinatal hypoxic-ischemic injury in M. nemestrina newborns. This model, which combines structural, biochemical, and behavioral assessments over time can be used to assess the safety and efficacy of neuroprotective strategies.