Etiologic factors in neonatal middle cerebral artery infarction are heterogenous. We evaluated 20 patients (5 days-7 years) in whom cerebral infarction was diagnosed on CT or ultrasound. Cases were ascertained through direct referral (13) and retrospective chart review of neonatal seizures (7). Details of the prenatal course, labor, delivery, placental examination, clinical course and laboratory and radiologic evaluations were reviewed. Significant findings included a high proportion of term babies (16). Maternal age and birth weight distributions were normal except for 2 severely growth retarded premature infants. Symptoms of asphixia were present in only 4 infants. Placental examinations were abnormal in 9/14 cases. CT/ultrasound findings were consistent with probable prenatal infarction in the distribution of the middle cerebral artery. Protein C levels were low initially in 4/12 infants; 1 remains low at 6 months of age. 3/8 tested mothers had low positive titers for anticardiolipin antibodies. A rational approach to the neonatal stroke should include specific attention to placental pathology and infant coagulation parameters. Increased utilization of CT scans in neonatal seizures as well as assessment and long term follow-up should lead to improved etiologic understanding of this complex problem.