AIM: To investigate if the serum biomarkers of cerebral injury, neuron-specific enolase and S100b protein, may classify unfavourable neurological outcome after paediatric cardiac arrest. METHODS: We performed a retrospective study of neuron-specific enolase and S100b measurements from 95 children treated in our paediatric cardiac intensive care unit after cardiac arrest. Neurological outcome at discharge was evaluated using the paediatric cerebral performance category scale, with unfavourable outcome defined as a change of >1 compared to pre-arrest status or death. RESULTS: Fifty-eight patients (61.1%) survived to discharge with 48 (50.5%) having a favourable neurological outcome. We observed significantly higher levels of both biomarkers in the unfavourable outcome group at designated time points (neuron-specific enolase at 24, 48, and 72h and S100b at 12, 24, and 48h after cardiac arrest, p<0.05). Receiver operating characteristic areas under the curve for neuron-specific enolase were 0.83, 0.80, and 0.73 at time points 24, 48, and 72h and 0.87, 0.81, and 0.82 for S100b at 12, 24, and 48h after cardiac arrest, respectively. Neuron-specific enolase measurement at 24h after cardiac arrest was an independent predictor of unfavourable outcome in a multivariable analysis. CONCLUSIONS: Neuron-specific enolase and S100b classify unfavourable neurological outcome in this large paediatric cardiac arrest cohort. Further multi-institutional prospective studies to comprehensively evaluate the diagnostic accuracy of these biomarkers under various clinical conditions and to determine reliable cut-off values in children are warranted.