New-onset atrial fibrillation (AF) occurs frequently in patients after cardiac surgery. The purpose of this study was to review the published trials and to provide clinical practice guidelines for pharmacologic prophylaxis against postoperative AF. Trials of pharmacologic prophylaxis against AF after heart surgery were identified by searching MEDLINE, the Cochrane Controlled Trials Register, and the bibliographies of published reports. Evidence grades and clinical recommendation scores were assigned to each prophylactic drug based on published evidence. Ninety-one trials were identified. The primary study design was a randomized, controlled trial of one drug vs placebo/usual care. Pharmacologic therapies that are reviewed include Vaughan-Williams class II agents (ie, β-receptor antagonists) [29 trials; 2,901 patients], Vaughan-Williams class III agents (ie, sotalol and amiodarone) [18 trials; 2,978 patients], Vaughan-Williams class IV agents (ie, verapamil and diltiazem) [5 trials; 601 patients], and Vaughan-Williams class I agents (ie, quinidine and procainamide) [3 trials; 246 patients], as well as digitalis (10 trials; 1,401 patients), magnesium (14 trials; 1,853 patients), dexamethasone (1 trial; 216 patients), glucose-insulin-potassium (3 trials; 102 patients), insulin (1 trial; 501 patients), triiodothyronine (2 trials; 301 patients), and aniline (1 trial; 32 patients). A consistent finding in this review is that antiarrhythmic drugs with β-adrenergic receptor-blocking effects (ie, class II beta-blockers, sotalol, and amiodarone) demonstrated successful prophylaxis. Furthermore, those therapies that did not inhibit β-receptors generally failed to demonstrate a decreased incidence in postoperative AF. While sotalol and amiodarone have been shown in some studies to be effective, their safety and the incremental prophylactic advantage in comparison with beta-blockers has not been conclusively demonstrated. On the basis of evidence that has been reviewed and graded for quality, it is recommended that strong consideration should be given to the prophylactic administration of Vaughan-Williams class II beta-blocking drugs as a means of lowering the incidence of new-onset post-cardiac surgery AF.