Abstract Funding Acknowledgements Type of funding sources: None. Background Polypharmacy has been defined as the daily use of more than 4 drugs, by an individual, regardless of the condition(s) they have been prescribed for and their efficacy. The burden of polypharmacy pertains to adverse drug reactions, disability, frequent and longtime hospitalization and long-term mortality. The prevalence of polypharmacy exceeds 10% in most adult age groups and particularly in the elderly. At the same time, atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, afflicting more than 8% of the elderly and those with multiple comorbidities. Purpose The purpose of this study was to examine the association between the presence of polypharmacy and outcomes among AF patients. Methods This is a retrospective analysis among 1140 patients enrolled in the MISOAC-AF trial. All cause- and cardiovascular- mortality have been defined as primary endpoints. Independent clinical predictors of polypharmacy and of major adverse outcomes were identified via bootstrapped multivariate logistic and Cox regression analysis, respectively. Results The mean number of prescribed medications at patients’ discharge was 3.9 ± 1.6 and polypharmacy (use of more than 4 medications daily) was found in 36.9% of the patients. Smoking (p = 0.036), dyslipidemia (p < 0.001), coronary artery disease (p < 0.001), heart failure (HF; p = 0.003) and chronic kidney disease (p < 0.001) were independent predictors of polypharmacy among AF paients. Kaplan–Meier survival analysis showed that AF patients with polypharmacy have significantly greater risk of CV death (p = 0.040), while Cox regression analysis indicated polypharmacy as an independent predictor for all-cause and CV- mortality [adjusted hazard ratios: 1.31(1.03 - 1.67) and 1.39(1.05 - 1.84), respectively] and for the composite outcome of AF- or HF- related hospitalization or CV death [adjusted hazard ratio: 1.31 (1.05 - 1.63)]. Conclusion This study highlights the implications of polypharmacy in the context of AF, a prevalent, chronic, life-threatening condition. Investigating polypharmacy is quite relevant in the era of pharmacovigilance, contributing to rational pharmacotherapy with regard to cardiovascular conditions and beyond. Abstract Figure. Mortality rates by polypharmacy presence