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End-stage renal disease (ESRD) is associated with increased cardiovascular morbidity and mortality. Recent studies indicate that atrial fibrillation (AF) is prevalent among ESRD patients while it adversely affects the clinical outcome. Despite these considerations, AF management in this population is problematic. Notably, most ESRD patients with AF are deprived of the benefits of anticoagulation therapy because of the fear of hemorrhagic complications. This article provides a concise and critical overview of the complex pathophysiology, epidemiology, and discusses the clinical issues regarding the emerging association between ESRD and AF.