Within a single-center prospective cohort study of neonatal encephalopathy involving 315 subjects, 15 neonates were found to have a focal stroke on magnetic resonance imaging. These 15 patients were matched on the basis of gender and degree of encephalopathy to 30 neonates without stroke from the same cohort. On Bayley Scales of Infant Development, the stroke group had Mental Development Index scores that were 1.7 standard deviations lower compared with controls (P = .007). This association was no longer seen after adjustment for the presence of neonatal seizures (P = .11). Of the 15 patients with stroke, 5 had been treated with hypothermia. None of these 5 had seizures in the neonatal period, compared with 7 of the untreated 10. This is the first human study to demonstrate a potential treatment effect of therapeutic hypothermia on perinatal stroke. It was also shown that seizures are associated with worse cognitive outcomes for stroke that presents with encephalopathy.