OBJECTIVE To assess whether amiodarone, as part of a strategy to achieve sinus rhythm, is safe and effective compared with a placebo or rate control drug in patients with persistent atrial fibrillation (AF) of more than 30 days' duration. METHODS Randomized controlled trials comparing amiodarone with a placebo or rate control drug were identified through the EMBASE (January 1, 1988, to October 18, 2008), MEDLINE (January 1, 1966, to October 18, 2008), and Cochrane Controlled Trials Register (second issue 2008) databases with no language restrictions. RESULTS Twelve randomized controlled trials that involved a total of 5060 patients with persistent AF were considered. Amiodarone was more effective than a placebo or rate control drug in achieving sinus rhythm (21.3 vs 9.2 per 100 patient-years in sinus rhythm; relative risk [RR], 3.2; 95% confidence interval [CI], 1.9-5.5), and its use was not associated with an increased risk of long-term mortality (4.7 vs 3.9 per 100 patient-years; RR, 0.95; 95% CI, 0.8-1.1; P=.51; I2=0%). Cessation of amiodarone therapy because of intolerable adverse effects was more common compared with a placebo or rate control drug (10.7 vs 1.9 per 100 patient-years; RR, 3.0; 95% CI, 1.4-6.2; P<.001; I2=70%), but amiodarone was not associated with an increased incidence of hospitalizations (RR, 1.1; 95% CI, 0.6-2.1; P=.77; I2=90%). CONCLUSION Amiodarone, as part of a strategy to achieve and maintain sinus rhythm, appears to be safe and effective in patients with persistent AF. However, some patients may not tolerate the adverse effects of this agent.