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To compare the efficacy and safety of lacosamide versus phenytoin for seizure prophylaxis following TBI.All TBI patients who received prophylaxis with either phenytoin or lacosamide were retrospectively identified. The incidence of seizures within the first 7days of injury were compared along with adverse effects requiring drug discontinuation. A planned sub-group analysis was performed for patients with severe TBI (GCS<9).There were 481 patients (phenytoin, n=116; lacosamide, n=365). Demographics were similar but age (50±21 vs 58±22years, P<.001) and initial GCS (11.3±4.3 vs 12.5±3.8, P=.010) were lower in the phenytoin group. The need for mechanical ventilation was higher (53% vs 38%, P=.004). Seizures occurred in 0.9% of the phenytoin group and 1.4% of the lacosamide group (P=1.00). ADEs were significantly higher with phenytoin (5.2% vs 0.5%, P=.003). This difference remained significant upon multivariate analysis [OR(95% CI)=9.4(1.8–48.9)]. Subgroup analysis for patients with severe TBI revealed no difference in seizures (phenytoin, 0% vs lacosamide, 1.5%; P=1.00) but more ADEs with phenytoin (12.5% vs 0%, P=.010).There was no difference between lacosamide and phenytoin in the prevention of early post traumatic seizures in patients following TBI. Lacosamide may have a more tolerable side effect profile.The incidence of early post-traumatic seizures following TBI is low.No difference was noted in seizure rate between phenytoin and lacosamide in this cohort.There were more adverse drug events with phenytoin compared to lacosamide.Future prospective trials are justified to validate the role of lacosamide for this indication.