BACKGROUND The standard for early posttraumatic brain injury (TBI) seizure prophylaxis is phenytoin. Despite its effectiveness, some argue for the use of newer antiepileptics (e.g., levetiracetam) because phenytoin requires close monitoring to maintain its therapeutic window and is associated with rare cutaneous hypersensitivity reactions. The purpose of this study was to evaluate whether phenytoin or levetiracetam would be more cost-effective in preventing early post-TBI seizures and reducing their negative impact on TBI outcomes. METHODS Cost-effectiveness analysis with the following base case assumptions: (1) phenytoin patients receive 1.0 g fosphenytoin load + 3 days of 100 mg three times a day (TID), have level drawn on day 3, "therapeutic" patients receive 100 mg TID on days 4 to 7, and "subtherapeutic" patients receive 200 mg TID on days 4 to 7; (2) levetiracetam patients receive 500 mg load + 7 days of 500 mg two times a day. Glasgow Outcome Scale (GOS) scores 4 to 5 represent good outcome, and GOS scores 2 to 3 represent poor outcome. Patients who develop early seizures: 40% good outcome, 50% poor outcome, and 10% death. Those who do not develop seizures: 75% good outcome, 20% poor outcome, and 5% death. Quality of life outcomes by GOS: good = 0.7, poor = 0.3, and death = 0.0. Severe adverse events and those impacting costs are rare for each agent. Assumptions were obtained through hospital query and exhaustive literature review. RESULTS The cost of a 7-day course of fosphenytoin, phenytoin, and free phenytoin level was $37.50, whereas the cost of a 7-day course of levetiracetam was $480.00. Literature review noted phenytoin to be as effective as levetiracetam in preventing early post-TBI seizures (and more effective in subclinical seizures). Quality-adjusted life years (QALY) were 23.6 for phenytoin and 23.2 for levetiracetam. As a result, the cost/effectiveness ratios were $1.58/QALY for phenytoin and $20.72/QALY for levetiracetam. All sensitivity analyses favored phenytoin unless levetiracetam prevented 100% of seizures and cost <$400 for 7-day course. CONCLUSIONS Phenytoin is more cost-effective than levetiracetam at all reasonable prices and at all clinically plausible reductions in post-TBI seizure potential.