A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth, predicts adverse neurodevelopmental outcome eighteen months after neonatal encephalopathy. We performed next generation sequencing on whole blood ribonucleic acid obtained within six hours of birth from the first 47 encephalopathic babies recruited to the Hypothermia for Encephalopathy in Low and middle-income countries (HELIX) trial. Two infants with blood culture positive sepsis were excluded, and the data from remaining 45 were analysed. A total of 855 genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1 and SMC4 were the most significant. Biological pathway analysis adjusted for gender, trial randomisation allocation (cooling therapy versus usual care) and estimated blood leukocyte proportions revealed over-representation of genes from pathways related to melatonin and polo-like kinase in babies with adverse outcome. These preliminary data suggest that transcriptomic profiling may be a promising tool for rapid risk stratification in neonatal encephalopathy. It may provide insights into biological mechanisms and identify novel therapeutic targets for neuroprotection. Neonatal encephalopathy (NE) related to perinatal asphyxia is the most common cause of death and neurodisability in term babies with an incidence of 2 to 3 per 1,000 live births in high-income countries, and 10 to 20 per 1,000 livebirths in low and middle-income countries 1,2. In high income countries, therapeutic hypothermia partially improves outcomes, although adverse outcomes still occur in up to 30% of the cooled infants 3. As the underlying brain injury evolves over hours and days after birth, early identification of at-risk encephalopathic infants is challenging and often inaccurate, particularly in cooled infants 4. Furthermore, NE is heterogenous condition resulting from a multitude of aetiologies including acute or sub-acute perinatal hypoxia,