Objective: Acute brain injury (ABI) is a catastrophic event, leading to disruption of the normal cerebral metabolic pathways and a subsequent cerebral energy deficit. Ketones (beta-hydroxybutyrate (BHB) and acetoacetate) may represent an alternative metabolic substrate with the potential to improve cerebral energy supply and decrease injury. The purpose of this study was to evaluate baseline ketone concentrations in the ABI population. Methods: Thirty-eight patients with ABI were enrolled into the study and followed for up to 7 days. We collected arterial blood samples immediately after admission and daily to measure the levels of BHB and acetoacetate. Where possible, matching cerebrospinal fluid (CSF) specimens were also collected. Results: During the study period, plasma BHB levels were increased initially but normalized by day 3 while acetoacetate levels remained within the normal range. The change in BHB was significant. There were 30 observations in 10 patients where BHB could be measured in both blood and CSF. When the data were averaged over patients there was a weak correlation between blood and CSF BHB (Spearman’s ρ = 0.62, p = 0.054). Conclusion: Blood ketone concentrations remain low within the ABI population. An external source of ketones will be required to increase blood concentrations to clinically relevant levels.