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Background: Intravenous recombinant tissue plasminogen activator (IV rtPA) is a recommended thrombolytic for the treatment of acute ischemic stroke that has shown to improve outcomes in various trials, but its cost-utility within varying time windows has not been systematically reviewed.Method: A systematic review was conducted using 2 reviewers and 1 adjudicator. Search strategies were implemented in PUBMED/MEDLINE, EMBASE, Web of Science, and Cochrane Review. Forms and data were managed through RedCap. Studies that met specific inclusion criteria, such as authors citing the time window and analytic horizon they investigated, and specifying the type of model they implemented, were further assessed for cost-utility benefit.Results: Of the 385 results from the implemented search strategy, 18 studies met inclusion criteria, with 94% agreement between reviewers. Eleven studies looked at the time window within 3 hours of stroke symptom onset, 3 looked between 3 to 4.5 hours, 3 looked within 4.5 hours of onset, and 1 looked within 6 hours of onset. All but 1 study with an analytic horizon of 1 year looking at a 0-3 hour time window showed that that IV rtPA was either dominant or cost-effective at a willingness to pay of $50,000/QALY.Conclusion: IV rtPA shows to be cost-effective across a variety of assumptions, both at a national and international level. The analytic horizon and time window do significantly impact the cost-effectiveness of IV rtPA, but even at later time windows, the IV rtPA shows to be cost-effective relative to standard treatment and care.