Although the use of amiodarone for the treatment of atrial fibrillation has increased, reports of its use for the restoration of sinus rhythm have been conflicting. In a recent prospective, randomized, single-blind, placebo controlled study, we examined the efficacy and safety of amiodarone as initial treatment to restore sinus rhythm in patients with atrial fibrillation of varying duration. We studied 335 patients (169 men, 166 women), aged 27-78 years (mean age 65 +/- 10 years), with symptomatic atrial fibrillation, who presented to the emergency room or to our clinic. Patients randomized to amiodarone ( n = 173) received 300 mg intravenously over 1 hour followed by 20 mg/kg over 24 hours. Oral administration was initiated simultaneously at 600 mg/day in 3 divided doses for one week followed by 400 mg/day, in two doses, for three weeks. Amiodarone was almost twice as likely as placebo to restore sinus rhythm (85% vs. 43%, p < 0.0001). Larger left atrial size and longer duration of atrial fibrillation decreased amiodarone's effectiveness. These factors were also associated with longer duration of treatment before conversion to sinus rhythm. We observed relatively few and only minor complications despite relatively high doses of amiodarone administered to achieve high serum concentrations. In conclusion, our findings indicate that amiodarone is an effective and safe antiarrhythmic drug even when administered in large doses. It may be used for the restoration of sinus rhythm when rapid cardioversion is not needed.