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Antiepileptics used for seizure prophylaxis after traumatic brain injury (TBI) are reviewed.Of the 275,000 people who are hospitalized with TBI each year, approximately 5–7% experience a posttraumatic seizure (PTS). According to the latest guidelines issued by the Brain Trauma Foundation and the American Academy of Neurology (AAN) for the management of severe TBI, PTS prophylaxis is recommended only during the first seven days after TBI. Of the available antiepileptic drugs, phenytoin has been the most extensively studied for the prophylaxis of PTS. Phenobarbital, valproate, and carbamazepine have not been as extensively researched, and, given their adverse-effect profiles and pharmacodynamic properties, there is no advantage to using these agents over phenytoin. Levetiracetam has demonstrated comparable efficacy to phenytoin for PTS prophylaxis and is associated with fewer adverse effects and monitoring considerations; it may be a reasonable alternative to phenytoin. However, levetiracetam has been associated with an increased seizure tendency. The Brain Trauma Foundation recommends using phenytoin for early PTS prophylaxis. The guidelines also state that valproate has demonstrated similar efficacy to phenytoin but warn that its use may be associated with increased mortality.The available literature supports the use of antiepileptics for early PTS prophylaxis during the first week after a TBI. Phenytoin has been extensively studied for this indication and is recommended by the AAN and Brain Trauma Foundation guidelines for early PTS prophylaxis. Levetiracetam has demonstrated comparable efficacy to phenytoin for early PTS prophylaxis and may be a reasonable alternative to consider in this patient population.