BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a rare neonatal condition affecting about 1‰ births. Despite a significant improvement in the management of this condition in the last ten years, HIE remains associated with high rates of death and severe neurological disability. From September 2015 to March 2017, a French national cohort of HIE cases was conducted to estimate the extent of long-term moderate and severe neurodevelopmental disability at 3 years and its determinants. METHODS: This prospective population-based cohort includes all moderate or severe cases of HIE, occurring in newborns delivered between 34 and 42 completed weeks of gestation and admitted to a neonatal intensive care unit. Detailed data on the pregnancy, delivery, and newborn until hospital discharge was collected from the medical records in maternity and neonatology units. All clinical examinations including biomarkers, EEG, and imaging were recorded. To ensure the completeness of HIE registration, a registry of non-included eligible neonates was organized, and the exhaustiveness of the cohort is currently checked using the national hospital discharge database. Follow-up is organized by the regional perinatal network, and 3 medical visits are planned at 18, 24 and 36 months. One additional project focused on early predictors, in particular early biomarkers, involves a quarter of the cohort. DISCUSSION: This cohort study aims to improve and update our knowledge about the incidence, the prognosis and the etiology of HIE, and to assess medical care. Its final objective is to improve the definition of this condition and develop prevention and management strategies for high-risk infants.