Traumatic brain injury (TBI) causes selective hippocampal cell death, which is believed to be associated with cognitive impairment observed both in clinical and experimental settings. Although neurotrophin administration has been tested as a strategy to prevent cell death following TBI, the potential neuroprotective role of neurotrophin-4/5 (NT-4/5) in TBI remains unknown. We hypothesized that NT-4/5 would offer neuroprotection for selectively vulnerable hippocampal neurons following TBI. Measurements of NT-4/5 in rats subjected to lateral fluid percussion (LFP) TBI revealed two–threefold increases in the injured cortex and hippocampus in the acute period (1–3 days) following brain injury. Subsequently, the response of NT-4/5 knockout (NT-4/5–/–) mice to controlled-cortical impact TBI was investigated. NT-4/5–/– mice were more susceptible to selective pyramidal cell loss in Ahmon's corn (CA) subfields of the hippocampus following TBI, and showed impaired motor recovery when compared with their brain-injured wild-type controls (NT-4/5wt). Additionally, we show that acute, prolonged administration of recombinant NT-4/5 (5 µg/kg/day) prevented up to 50% of the hippocampal CA pyramidal cell death following LFP TBI in rats. These results suggest that post-traumatic increases in endogenous NT-4/5 may be part of an adaptive neuroprotective response in the injured brain, and that administration of this neurotrophic factor may be useful as a therapeutic strategy following TBI.