It is common practice to prescribe prophylactic antiepileptic drugs (AED) to high-grade glioma (HGG) patients without a history of seizures, yet with limited evidence supporting its use. Ideally, the effectiveness of prophylactic anticonvulsants must outweigh the occurrence of adverse effects and interactions related to AED. The authors conducted a systematic review and metanalysis of longitudinal studies regarding the effectiveness of prophylactic AED in seizure-naïve HGG patients. PubMed/MEDLINE, Cochrane Central Register of Controlled trials, Embase and clinicaltrials.gov databases were systematically searched. Of the initial 1773 studies identified, 15 were finally selected for data extraction and analysis. Heterogeneity among studies, pooled hazard ratios, publication bias and sensitivity analyses were performed separately for a 15-study group (HGG patients within larger series of brain tumors) and a 6-study group (exclusively HGG patients). AED prophylaxis did not significantly reduce the incidence of postoperative seizures compared with controls, both in the 15-study group (Mantel-Haenszel random-effects pooled OR 1.08, 95% CI 0.82-1.43, 2123 patients) and in the 6-study group (pooled OR 1.22, 95% CI 0.77-1.92, 540 patients). However, some issues (paucity of prospective trials, overall moderate-risk of bias, and few studies addressing HGG patients exclusively) preclude firm conclusions against routine prophylactic AED prescription. Reported adverse effects attributable to AED were acceptable in the majority of studies. Within the limitations of this review, the results of this metanalysis do not support the routine administration of prophylactic AED to HGG patients without a history of seizures.