Abstract Body: INTRODUCTION: Reperfusion injury after cardiac arrest (CA) leads to poor survival and neurological outcomes. We hypothesized that a combination of pharmacologic neuroprotection therapies administered 24-72 hours post-CA [“combination therapy”] that target key steps in reperfusion injury; 1) excitotoxicity (Magnesium, Memantine, Perampanel, Minocycline), 2) mitochondrial dysfunction (Thiamine, Coenzyme Q10), 3) oxidative stress (Vitamin C, Vitamin E), and 4) inflammation (Hydrocortisone), would improve survival. AIMS: We compared survival between subjects with combination therapy and those without. METHODS: A retrospective analysis of post-CA patients (01/01/2019 - 06/01/2023) was conducted as part of a quality improvement project. Inclusion: in-hospital CA, age ≥ 18 years, non-COVID, ≥ 5 min CPR, sustained ROSC (≥ 20 min). Exclusion: out-of-hospital CA. Combination therapy was at the discretion of the provider and given in addition to current post-CA standard critical care: targeted temperature management (TTM) (32-36°C), glucose (target 140 mg/dL), PaO2 (target 100 mmHg), PaCO2 (target 40 mmHg), and MAP (target 80 - 100 mmHg). Survival was assessed at hospital discharge. RESULTS: Among 196 subjects, 146 received combination therapy (study group) and 50 did not (control group). Demographic variables (age, race, ethnicity) and intra-cardiac arrest variables (initial rhythm, CPR duration, and hospital site) were not statistically different between groups. Post-CA variables (mean PaCO2, PaO2, and glucose) were not statistically different between groups. MAP was 76 (69, 83) for study group and 65 (46, 72) for control group (P = <0.001). Lowest temperature in study group was 34.8°C vs. 35.9°C in control group (P = 0.034). Survival at hospital discharge was 33% for study group and 14% for control group (P = 0.01). There were no known safety concerns or adverse events. CONCLUSIONS: The administration of a combination of neuroprotective medications that target key pathways in reperfusion injury appears to be feasible and safe, and may improve survival beyond current post-CA standard critical care. A future randomized controlled trial that includes the assessment of neurological outcomes is warranted.