Our hypothesis was that among infants with hypoxic-ischemic encephalopathy (HIE), venoarterial (VA), compared to venovenous (VV), extracorporeal membrane oxygenation (ECMO) is associated with an increased risk of mortality or intracranial hemorrhage (ICH). Retrospective cohort analysis of infants in the Children's Hospitals Neonatal Database from 2010 to 2016 with moderate or severe HIE, gestational age ≥36 weeks, and ECMO initiation <7 days of age. The primary outcome was mortality or ICH. Severe HIE was more common in the VA ECMO group (n = 57), compared to the VV ECMO group (n = 53) (47.4% vs. 26.4%, P = 0.02). VA ECMO was associated with a significantly higher risk of death or ICH 57.9% vs. 34.0%, aOR 2.39 (1.08-5.28) and mortality 31.6% vs. 11.3%, aOR 3.06 (1.08-8.68), after adjusting for HIE severity. In HIE, VA ECMO was associated with a higher incidence of mortality or ICH. VV ECMO may be beneficial in this population.