Traumatic brain injury (TBI) can cause life-changing neurological deficits. There are currently no neuroprotective treatments in TBI. The high content of oxidation-sensitive polyunsaturated fatty acids (PUFAs) in the brain generates an environment vulnerable to TBI-related oxidative damage. We hypothesised that partial replacement of tissue PUFAs with deuterium - enriched PUFAs (D-PUFAs), could act as a brake against oxidation and improve outcome.A moderately severe TBI was induced using a controlled cortical impact (CCI) in adult male and female CD1 mice. Animals received a control or a D-PUFA-enriched diet for 40 days before and 14 days post-injury. The D-PUFAs forms provided were arachidonic acid (ARA) and docosahexaenoic acid (DHA). Up to 70% D-PUFA incorporation levels were achieved in tissue. Behavioural analysis (modified neurological severity score, Rotarod and elevated zero maze) revealed no significant differences in outcome between the D-PUFA diet and control diet groups. Immunohistological analysis of the cortex and hippocampus with markers for astrocytes (GFAP), microglia/macrophages (IBA1) and nucleic acid oxidation (8oxo) indicated a complex response to injury in both sexes, and some beneficial impact of D-PUFA supplementation, which was more pronounced in males. Perilesional 8oxo expression in cortex was significantly decreased by 50% or more in both sexes, while GFAP and IBA1 levels were also attenuated by treatment. Hippocampal tissue showed a similar effect profile.These results suggest that D-PUFA enrichment in the brain before traumatic injury may exert some tissue protection. The potential impact on neurological outcome, especially at later times after injury, has to be further explored.