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Atrial fibrillation is a common problem following cardiac surgery. Atrial fibrillation occurs in 30% to 50% patients during postoperative period. Postoperative atrial fibrillation often results in increased length of hospital stay, increased cost of postoperative hospitalization, heart failure, and, less frequently, cerebrovascular accident and death. Because postoperative atrial fibrillation is such a significant problem, several studies have attempted to find a safe and effective treatment for its prevention. In this article, we review the evidence for various prophylactic therapies and make an attempt to answer the following: (1) Can postoperative atrial fibrillation be prevented? (2) Is prophylactic therapy for postoperative atrial fibrillation safe? (3) Does prevention of postoperative atrial fibrillation prevent adverse outcomes associated with it? Evidence for safety and efficacy or lack of β-blockers, sotalol, amiodarone, intravenous magnesium, and atrial pacing is reviewed and current recommendations by the American College of Cardiology/American Heart Association/European Society of Cardiology are presented.