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BackgroundHyperthermia after hypoxia–ischemia (HI) in newborn infants is associated with worse neurological outcomes. Loss of thermoregulation may also be associated with greater injury.MethodsIn the postnatal-day 7 (P7) rat, the effect of 5 h of graded hyperthermia (38 °C or 39 °C) immediately after unilateral HI was compared with normothermia (NT, 37 °C) and therapeutic hypothermia (TH, 32 °C). Early (negative geotaxis) and late (staircase test) behavioral testing was performed, as well as neuropathology scoring in adulthood. Separately, P7 rats were exposed to HI, and individual nesting temperatures were monitored before analysis of neuropathology at P14.ResultsMortality increased as temperature was increased from 38 °C (0%) to 39 °C (50%) after HI. Hyperthermia also resulted in early behavioral deficits compared with NT. In adulthood, pathology scores in the thalamus, basal ganglia, cortex, and hippocampus increased as post-hypoxic temperature increased above NT. Significant global neuroprotection was seen in the TH group. However, no significant difference was seen between HI groups in the staircase test. One hour after HI, the core temperature of pups was inversely correlated with global pathology scores at P14.ConclusionEarly temperature is a significant determinant of injury after experimental HI. Spontaneous decreases in core temperature after HI may confound neuroprotection studies.