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Objective: Central nervous system (CNS) derived exosomes can be purified from peripheral blood and have been used widely in adult neurological disease. Application to neonatal neurological disease deserves investigation in the setting of hypoxic-ischaemic encephalopathy (HIE)., Design: Observational cohort., Setting: Level III neonatal intensive care unit., Participants: Term/near-term neonates undergoing therapeutic hypothermia (TH) for HIE., Interventions: Blood samples were collected at 0-6, 12, 24, 48 and 96 hours of life., Main Outcomes and Measures: CNS exosomes were purified from serum using previously described methods. Biomarker protein levels were quantified using standard ELISA methods and normalised to exosome marker CD-81. The slope of change for biomarker levels was calculated for each time interval. Our primary outcome was MRI basal ganglia/watershed score of ≥3., Results: 26 subjects were included (umbilical artery pH range 6.6-7.29; 35% seizures). An increasing MRI injury score was significantly associated with decreasing levels of synaptopodin between 0-6 and 12 hours (p=0.03) and increasing levels of lipocalin-2 (NGAL) between 12 and 48 hours (p<0.0001). Neuronal pentraxin was not significant. The negative predictive values for increasing synaptopodin and decreasing NGAL was 70.0% and 90.9%, respectively., Conclusions and Relevance: Our results indicate that CNS exosome cargo has the potential to act as biomarkers of the severity of brain injury and response to TH as well as quantify pharmacological response to neuroactive therapeutic/adjuvant agents. Rigorous prospective trials are critical to evaluate potential clinical use of exosome biomarkers., Competing Interests: Competing interests: LG has a patent for isolating fetal/neonatal neural exosomes using Contactin-2, but there is no current commercial use., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)