OBJECTIVE: To investigate the association of neonatal hypoglycaemia and hyperglycaemia with outcomes in infants with hypoxic ischaemic encephalopathy (HIE). DESIGN: Post hoc analysis of the CoolCap Study. SETTING: 25 perinatal centres in the UK, the USA and New Zealand during 1999-2002. PATIENTS: 234 infants at ≥36 weeks' gestation with moderate-to-severe HIE enrolled in the CoolCap Study. 214 (91%) infants had documented plasma glucose and follow-up outcome data. INTERVENTION: Infants were randomised to head cooling for 72 h starting within 6 h of birth, or standard care. Plasma glucose levels were measured at predetermined time intervals after randomisation. MAIN OUTCOME MEASURE: The unfavourable primary outcome of the study was death and/or severe neurodevelopmental disability at 18 months. Hypoglycaemia (≤40 mg/dL, ≤2.2 mmol/L) and hyperglycaemia (>150 mg/dL, >8.3 mmol/L) during the first 12 h after randomisation were investigated for univariable and multivariable associations with unfavourable primary outcome. RESULTS: 121 (57%) infants had abnormal plasma glucose values within 12 h of randomisation. Unfavourable outcome was observed in 126 (60%) infants and was more common among subjects with hypoglycaemia (81%, p=0.004), hyperglycaemia (67%, p=0.01) and any glucose derangement within the first 12 h (67%, p=0.002) compared with normoglycaemic infants (48%) in univariable analysis. These associations remained significant after adjusting for birth weight, Apgar score, pH, Sarnat stage and hypothermia therapy. CONCLUSIONS: Both hypoglycaemia and hyperglycaemia in infants with moderate-to-severe HIE were independently associated with unfavourable outcome. Future studies are needed to investigate the prognostic significance of these associations and their role as biomarkers of brain injury. TRIAL REGISTRATION NUMBER: (ClinicalTrials.gov NCT00383305).