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Background Polypharmacy is highly prevalent in elderly people with chronic conditions, including atrial fibrillation (AF). The impact of polypharmacy on adverse outcomes and on treatment effectiveness in elderly patients with AF remains unaddressed. Methods and Results We studied 338 810 AF patients ≥75 years of age enrolled in the MarketScan Medicare Supplemental database in 2007-2015. Polypharmacy was defined as ≥5 active prescriptions at AF diagnosis (defined by the presence of International Classification of Diseases, Ninth Revision, Clinical Modificati