To identify risk factors for hypoxic-ischemic encephalopathy (HIE) within a recent US birth cohort. In a retrospective cohort study of 44 572 singleton infants ≥36 weeks of gestation born at Kaiser Permanente Northern California in 2008-2015, we identified all infants with HIE based on the presence of 3 inclusion criteria: clinical signs of neonatal encephalopathy, NICU admission, and either a 10-minute Apgar of ≤5 or a base excess of ≤-15 mmol/L. Neonatal acidemia was defined as a base excess of ≤-12 mmol/L. We ascertained antenatal and intrapartum complications from electronic records. Multivariable analysis was performed using logistic regression. There were 45 infants (1.0 per 1000) with HIE and 197 (4.4 per 1000) with neonatal acidemia. Of the infants with HIE, 64% had an intrapartum complication consisting of a sentinel event (36%), clinical chorioamnionitis (40%), or both (11%). Risk factors for HIE on multivariable analysis were sentinel event (relative risk RR, 16.1; 95% CI, 8.4-33) and clinical chorioamnionitis (RR, 5.2; 95% CI, 2.7-9.9). After removing the 16 infants with HIE who were exposed to a sentinel event from multivariate analysis, maternal age of ≥35 years (RR, 2.5; 95% CI, 1.1-5.6) and a urinary tract infection during pregnancy (RR, 2.6; 95% CI, 1.0-6.5) emerged as potential antenatal risk factors for HIE. A significant proportion of HIE is preceded by a sentinel event, emphasizing the importance of developing improved methodologies to predict and prevent this perinatal complication. Strategies focused on reducing other complications such as clinical chorioamnionitis and/or maternal pyrexia may also improve our ability to prevent HIE.