Background: Much debate exists on the optimal medication for posttraumatic seizure prophylaxis after traumatic brain injury (TBI). There is some evidence that levetiracetam (LEV) could be neuroprotective and provide long-term benefits in this patient population. Objective: The primary objective was to compare the Glasgow Outcome Scale–Extended (GOS-E) 6 months or more after severe TBI. Secondary end points were presence of early seizures (0 to 7 days post-TBI) or late seizures (8 days post-TBI to phone interview), use of anticonvulsant medication when interviewed, medication-related hospital complications, and a summary of phenytoin (PHT) and LEV dosing regimens. Methods: This was an IRB-approved, single-center, prospective cohort analysis. Patients were identified by cross-referencing a list of patients receiving LEV or PHT, with a list of patients with ICD-9 code consistent with TBI. After study inclusion, patients were contacted by telephone, and the GOS-E was administered. Data for secondary end points were gathered by retrospective chart review. Results: In all, 19 patients were included in the final analysis. There was no difference in the GOS-E score assessed ≥6 months after injury (5.07 ± 1.69 vs 5.60 ± 2.07, P = 0.58). There was no difference in the secondary end points of early seizures (P = 0.53) or late seizures (P = 0.53). However, the PHT group experienced a higher rate of hospital days with recorded fever (0.20 ± 0.22 vs 0 ± 0; P = 0.014). Conclusions: Long-term functional outcome in patients who experienced a TBI was not affected by treatment with PHT or LEV; however, patients treated with PHT had a higher incidence of fever during hospitalization.