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Despite many children experiencing fatigue after childhood brain injury, little is known about the predictors of this complaint. To date, traditional indices of traumatic brain injury (TBI) severity have not predicted reliably persisting fatigue (up to three years post-injury). This study aimed to establish whether persisting fatigue is predicted by serum biomarker concentrations in child TBI. We examined whether acute serum biomarker expression would improve prediction models of 12-month fatigue based on injury severity. Blood samples were collected from 87 children (1–17 years at injury) sustaining mild to severe TBI (Glasgow Coma Scale [GCS] range 3–15; mean 12.43; classified as mild TBI [n = 50, 57%] vs. moderate/severe TBI [n = 37, 43%]), and presenting to the emergency departments (ED) and pediatric intensive care units (PICU) at one of three tertiary pediatric hospitals (Royal Children's Hospital (RCH); Hospital for Sick Children (HSC), Toronto; St Justine Children's Hospital (SJH), Montreal). Six serum biomarker concentrations were measured within 24 h of injury (interleukin-6, interleukin-8 [IL-8], soluble vascular cell adhesion molecule [SVCAM], S100 calcium binding protein B [S100B], neuron specific enolase [NSE], and soluble neural cell adhesion molecule [sNCAM]). Fatigue at 12 months post-injury was measured using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (parent report), classified as present/absent using previously derived cut-points. At 12 months post-injury, 22% of participants experienced fatigue. A model including IL-8 was the best serum biomarker for estimating the probability of children experiencing fatigue at 12 months post-injury. The IL-8 also significantly improved predictive models of fatigue based on severity. [ABSTRACT FROM AUTHOR]