OBJECTIVES: To determine if infections involving the placenta are associated with unexplained systemic illness in the newborn infant and subsequent poor neonatal outcome (death or significant neurodevelopmental abnormalities). STUDY DESIGN: Placental tissue from 33 newborn infants with systemic illness and poor neonatal outcome were tested by in situ hybridization or reverse transcriptase-polymerase chain reaction for infectious pathogens. Control placentas came from mothers delivering infants with poor neonatal outcome of known cause (ie, cord prolapse, uterine rupture), mothers with known infections, and normal births (n=21). RESULTS: There were 5 deaths among the newborn infants, and all survivors had poor neonatal outcome. Placentas from 24 of 33 cases (73%) had positive test results for Coxsackie virus (46%), bacteria (38%), herpes (8%), and parvovirus (4%) and picornavirus (4%). At autopsy, multiple organs from the newborn infant had positive test results for the same organism isolated from the placenta. No infectious agents were detected in the control infants, except those from mothers with known infections. CONCLUSIONS: In utero infection of the placenta is associated with systemic illness in the newborn infant and poor neonatal outcome. These results emphasize the importance of pathologic and molecular examination of the placenta in critically ill newborn infants.