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Background: Postoperative atrial fibrillation/flutter (POAF) is associated with significant morbidity and mortality after general thoracic surgery, but the need for and the best agent for prophylaxis remains obscure., Methods: A systematic literature search was performed to identify randomized controlled trials that compared regimens for POAF prophylaxis after general thoracic surgery. Random-effects meta-analyses with trial sequential analyses were performed to compare the effects of medical prophylaxis vs placebo/usual care. The risk of POAF among patients receiving various prophylactic regimens was subjected to Bayesian network meta-analysis., Results: Twenty-two trials (2,891 patients and 11 regimens) were included. Overall, medical prophylaxis reduced the incidence of POAF (OR, 0.33; 95% CI, 0.22-0.49) but not short-term mortality (OR, 0.85; 95% CI, 0.41-1.73). There was no significant difference in patient withdrawal due to adverse events (OR, 1.67; 95% CI, 0.67-4.16). Trial sequential analysis showed that as of 2012, sufficient evidence had accrued in support of the effectiveness of medical prophylaxis in reducing POAF after general thoracic surgery. In network meta-analysis, β-blockers, angiotensin-converting enzyme inhibitors, amiodarone, magnesium, and calcium channel blockers significantly reduced the risk of POAF compared with placebo/usual care. β-Blockers had the highest probability of being the most effective agents (OR, 0.12; 95% credible interval [CrI], 0.05-0.27; probability of being best, 77.7%; number needed to treat, 5.2)., Conclusions: The current literature supports the effectiveness and tolerability of medical prophylaxis and the superiority of β-blockers in preventing POAF after general thoracic surgery. β-Blockers are recommended, taking into consideration the status of the bronchopulmonary system., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)