<h3>Objective:</h3> To evaluate the use of prophylactic anti-seizure medications (ASM) in seizure-naïve patients with newly diagnosed brain tumors <h3>Background:</h3> Many physicians continue to prescribe ASM to seizure-naïve brain tumor patients, even though treatment guidelines recommend against such practice. <h3>Design/Methods:</h3> In this retrospective observational study, electronic medical records from the TriNetX Dataworks – USA Network were used to identify patients with a record of brain tumor diagnosis and no evidence of seizure diagnosis from 2012 to 2017. Patients who were prescribed a prophylactic ASM were propensity-score (PS) matched with those who were not at a 1:1 ratio on age, sex, race, ethnicity, tumor types, comorbidities, prescription medications, and procedures. Prophylactic ASM use was defined as the prescription of ≥1 ASM from 30 days before the first brain tumor diagnosis and up to 30 days afterwards. Hazard ratios for seizure development and mortality were assessed using Cox proportional hazards regression models. The first brain tumor diagnosis date was considered the index date, and patients were followed up to 5 years from their first prescription record, death, or whichever occurred first. <h3>Results:</h3> Of the 117,834 seizure-naïve patients who were newly diagnosed with brain tumor, 18,963 (16.1%) were prescribed a prophylactic ASM. Of the 14,238 patients in each PS-matched cohort, 778 of those on prophylaxis (5.5%) and 452 of those not on prophylaxis (3.0%) developed a seizure during the follow-up period (Hazard Ratio: 2.3 [95% CI: 2.0, 2.6]). Mortality hazard was 1.1 times (95% CI: 1.1, 1.2) higher in those on prophylactic ASM. <h3>Conclusions:</h3> Seizure-naïve patients with brain tumor who were prescribed a prophylactic ASM had a higher hazard of developing a seizure compared with those who were not. Unobserved risk factors that were not controlled for may explain the apparent analysis results. Clinical trials are warranted to further examine this controversial disease management approach. <b>Disclosure:</b> Miss Jang has received personal compensation for serving as an employee of Eisai Inc.. Miss Jang has received research support from Eisai Inc.. Dr. Peters has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Vivacitas Oncology. Dr. Peters has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Servier. Dr. Peters has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sapience. Dr. Peters has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NuVox Therapeutics. Dr. Peters has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Cordance Medical. Dr. Peters has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ONO Pharmaceutical. Dr. Peters has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Blue Earth Diagnostics. The institution of Dr. Peters has received research support from Novocure. The institution of Dr. Peters has received research support from Biomimetix. The institution of Dr. Peters has received research support from Servier. The institution of Dr. Peters has received research support from Varian. The institution of Dr. Peters has received research support from Sapience. Dr. Peters has received personal compensation in the range of $500-$4,999 for serving as a Educational Lecturer with Eisai. Dr. Ngo has received personal compensation for serving as an employee of Eisai Inc.. An immediate family member of Dr. Morita-Sherman has received personal compensation for serving as an employee of Forrester Research. Dr. Morita-Sherman has received personal compensation for serving as an employee of Eisai Inc.. An immediate family member of Dr. Morita-Sherman has stock in Forrester Research. The institution of Dr. Morita-Sherman has received research support from Cleveland Clinic.