The effectiveness of seizure prophylaxis in controlling postoperative seizures following craniotomy for tumor resection is unclear. Most patients are seizure-free before surgery. To prevent seizures, it is common to treat tumor craniotomy patients postoperatively with an antiepileptic drug (AED). The authors retrospectively analyzed seizure occurrence with and without postoperative prophylactic AEDs. Between 2005 and 2011 at the authors' institution, 588 patients underwent craniotomy for brain tumors and were screened. Data on seizures, AED use, histopathology, comorbidities, complications, and follow-up were collected. Exclusion criteria included lack of follow-up data, previous operation, preoperative seizures, or preoperative AED prophylaxis. The incidence of postoperative seizures in patients with and without prophylactic AEDs was compared using logistic regression analysis. A total of 202 patients (50.5% female) were included. The most common tumor diagnosis was metastasis (42.6%). Of the 202 patients, 66.3% were prescribed prophylactic AED after surgery. Forty-six of 202 (22.8%) suffered a postoperative seizure. The odds of seizure for patients on prophylactic AED was 1.62 times higher than those not on AED (p = 0.2867). No difference was found in seizure occurrence between patients with glioblastoma multiforme compared with other tumor types (odds ratio 1.75, p = 0.1468). No difference was found in time-to-seizure between the two groups (hazard ratio 1.38, p = 0.3776). These data show no statistically significant benefit to prophylactic postoperative AED and a nonsignificant trend for increased seizure risk with AEDs. A randomized, placebo-controlled trial is needed to clarify the benefit of postoperative AED use for brain tumor resection.