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Background: Traumatic brain injury (TBI) is a major cause of morbidity and mortality in the United States. Older adults represent an understudied and growing TBI population. Current Brain Trauma Foundation guidelines support prophylactic antiseizure medication (ASM) administration to reduce the risk of early posttraumatic seizures (within 7 days of injury) in patients with severe TBI. Whether ASM decreases mortality or early seizure risk in this population remains unclear. This study addresses the knowledge gap regarding the impact of ASM administration on the risk of seizure or mortality after TBI in patients more than 65 years of age., Methods: This retrospective cohort study used a publicly available data set from the Medical Information Mart for Intensive Care-III from the Massachusetts Institute of Technology. Our cohort included patients 65 years or older with a primary exposure of early ASM administration with TBI resulting in an intensive care unit (ICU) admission in a level I trauma center from 2001 to 2012. A double-robust inverse propensity scale weighted model on the basis of proportional hazard and logistic regression models was created to assess the association between ASM administration and risk of death within 7 days of admission to the ICU. Secondary outcomes included 30-day mortality and 1-year mortality, early posttraumatic seizures, ICU length of stay, and hospital length of stay., Results: Of 1145 patients 65 years or older with TBI admitted to an ICU, 783 (68.4%) received ASM within the first 24 h. Patients meeting inclusion criteria were predominantly white (83.8%) and were male (52.3%), with a median (interquartile range) age of 81 (74-86) years. TBI severity, classified by Glasgow Coma Score, was predominantly mild (71.2%), followed by moderate (16.8%) and severe (11.3%). Patients who received ASM were less likely to have died at 7 days (adjusted death hazard ratio [HR] = 0.48 [95% confidence interval {CI} 0.28-0.88], P = 0.005), at 30 days (adjusted HR 0.67 [95% CI 0.45-0.99], P = 0.045), and at 1 year (adjusted HR 0.72 [95% CI 0.54-0.97], P = 0.029). Groups were not different in regard to seizure (adjusted seizure odds ratio 1.18 [95% CI 0.61-2.26]) compared with those who did not receive ASM., Conclusions: Early ASM administration was associated with reduced mortality at 7 days, 30 days, and 1 year but did not decrease the risk of early seizures among older adults who presented with TBI at an ICU. This benefit was observed in mild, moderate, and severe TBI assessed by Glasgow Coma Score on presentation among patients 65 years old and older and suggests broader recommendations for the use of ASM in older adults who present with TBI of any severity at an ICU., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)