OBJECTIVE: To investigate the protective role of lamotrigine (LTG), which has a neuroprotective effect on secondary damage induced in the head trauma model. STUDY DESIGN: Sixty-four rats were divided into 4 groups: group 1 (vehicle-treated control), group 2 (LTG 10 mg/kg/day), group 3 (vehicle-treated trauma), and group 4 (trauma+LTG 10 mg/kg/day). Distilled water was used as vehicle. All rats were decapitated 48 hours after the induction of trauma, and the protective effects of LTG were evaluated by histological, behavioral, immunohistochemical, and biochemical analyses. RESULTS: Administration of LTG at a dose of 10 mg/kg/day provided significant improvement in all of the histological, biochemical, and behavioral parameters after the induction of traumatic brain injury. Trauma caused a significant alteration in the neurological examination scores at 48 hours (p < 0.001). Although the scores were still higher in the LTG-treated group, it was significantly improved as compared with the trauma group (p < 0.01). CONCLUSION: In this study, histopathological scoring was performed in the control, trauma, and LTG groups. p < 0.0001 values were found to be significant in comparison between groups. Vascular endothelial growth factor expressions were compared between the groups. p < 0.0001 values were found to be significant. Glial fibrillary acidic protein expressions were compared between the groups. p=0.0004 values were found. Although further studies are necessary to evaluate the time-and-dose-dependent neuroprotective effects of LTG, it may be a beneficial therapeutic agent for prevention of secondary neuronal damage following diffuse traumatic brain injury. © Science Printers and Publishers, Inc.