Systemic hypoxia-ischemia at birth may alter the neonatal neutrophil phenotype. In this study, we evaluated alterations in perinatal neutrophil phenotype following systemic hypoxia-ischemia compared with normal controls. Neutrophils from adults (n = 15), normal newborns (n = 20), newborns requiring resuscitation at birth (n = 17), and their respective maternal samples were incubated alone or with lipopolysaccharide (LPS). Surface receptor CD11b (neutrophil activation) and the percentage apoptosis (persistence of inflammatory response) were assessed using flow cytometry. Neutrophil apoptosis was decreased in neonates requiring resuscitation at birth and was further exaggerated in infants who developed mild neurological signs. All infants who required resuscitation were LPS hyporesponsive irrespective of neurological findings. Newborns with severe neurological signs had increased apoptosis and decreased CD11b. Maternal neutrophils were LPS hyporesponsive only if their infants had moderate/severe neurological signs. Infants with mild encephalopathy may display a predominantly proinflammatory neutrophil response with a persistent inflammatory response, whereas those with moderate/severe encephalopathy have a tendency toward immunosuppression.