Each year thousands of Medicare beneficiaries routinely receive anti-seizure medication (ASM) for prophylaxis after a traumatic brain injury (TBI). These drugs are potentially life-saving given the severity of seizure sequelae, but also potentially life-threatening because of frequent, serious adverse events, e.g., falls. Older adults with Alzheimer’s Disease and Related Dementias (ADRD) are at higher risk for TBIs and post TBI complications. They are also more vulnerable to ASM adverse effects including cognitive slowing. Despite the known delicate balance between benefit and harm, there are no trial data to guide decisions about prophylaxis after a TBI among older adults, and particularly those with ADRD. The sparse and conflicted existing literature has been limited by the difficulty assessing relevant measures, e.g., TBI severity in large data sets. Medicare claims data offer potential, but lack well-validated definitions for TBI severity or treatment-related adverse effects. We will leverage multiple novel linked data sources: Traditional Medicare claims linked to a TBI registry and Electronic Health Records (EHR) of a large regional health system, and National Medicare linked to the Minimum Dataset (a national registry of post-acute institutionalized Medicare/Medicaid beneficiaries, 2009-2022). First, we will improve classification algorithms for TBI severity for use in common administrative databases. Then, we will assess a critical decision in the setting of moderate to severe TBI, particularly among those with ADRD: stopping prophylaxis within 7 days versus continuing. We will apply multiple state-of-the science analytical tools to address confounding and other challenges. We have three aims: 1) To improve classification algorithms for TBI severity for use in common administrative databases; 2) To examine the impact of the duration of ASM prophylaxis for post-TBI patients on 6-month event rates; and 3) To examine differences in treatment effects with preexisting ADRD status. This comparative effectiveness and safety study could inform future policy and clinical care and improve TBI and ADRD care, e.g., through adjustments in Medicare quality incentives and clinical guidelines. Moreover, these data could help inform patients, families, clinicians, and policy makers about how we can improve care the rapidly expanding population of patients with ADRD.