Neonatal encephalopathy (NE) remains an important cause of morbidity and mortality in the term infant, and many cases have an antepartum, rather than an intrapartum, etiology. Chronic processes such as thrombosis result in changes in the placenta. We sought to determine whether histopathological examination of the placenta in cases of NE, focusing on these changes, could identify significant antenatal processes that are not recognized by clinical assessment alone. Infants born at term with NE were identified retrospectively over a 12-year period. Placental tissue from deliveries during the study period was available for reexamination. Controls were selected from a cohort of 1000 consecutive deliveries on which clinical and pathological data were collected as part of an earlier study. Bivariate and multivariate analyses of clinical and pathological factors for cases and controls were used to test for an independent association with NE. Clinical and placental data was collected on 93 cases of NE and 387 controls. The placental features of fetal thrombotic vasculopathy (FTV), funisitis (signifying a fetal response to infection), and accelerated villous maturation were independently associated with NE. Of the clinical factors studied, meconium-stained liquor and abnormal cardiotocograph were independently associated. There were no independently associated clinical antenatal factors. Placental features of infection, thrombosis, and disturbed uteroplacental flow are significant independent factors in the etiology of NE in this study. Acute and chronic features suggest that NE may result from acute stress in an already compromised infant. The absence of significant clinical antenatal factors supports the value of placental examination in the investigation of infants with NE.