The use of antiepileptic drugs (AEDs) is effective in reducing the risk of developing early (acute symptomatic) post-traumatic seizures compared to placebo or usual care in patients with severe TBI (low-quality evidence). With regards to the choice of the AED, the available evidence supports the use of phenytoin, starting with an intravenous loading dose initiated as soon as possible after severe TBI]. Despite the lack of evidence from comparative clinical trials, levetiracetam is increasingly used in primary prevention of early post-traumatic seizures due to its ease of use, favorable safety profile and lack of pharmacokinetic interactions. So far, there is no evidence to support the use of other neuroprotective agents for the primary prevention of early post-traumatic seizures. Patients with early post-traumatic seizures do not generally require long-term AED treatment since their risk to develop post-traumatic epilepsy is low. High-quality and adequately powered trials conducted in a selected population at high risk of developing late post-traumatic seizures are required to draw definite conclusions on the effectiveness of long-term prophylactic treatment. Further studies to explore the antiepileptogenic and neuroprotective effects of anti-inflammatory and immune-modulatory therapies are also warranted.