Pharmacologic therapy is widely used for restoration of sinus rhythm and prevention of recurrences of atrial fibrillation. Because concerns have been raised about their potential proarrhythmic effects, therapeutic regimens should be evaluated by placebo-controlled studies to determine their efficacy and safety. One hundred thirty-six patients with persistent atrial fibrillation were randomized to receive propafenone 2 mg/kg over 30 minutes, followed by oral propafenone 150 mg 3 times daily or matching placebo. Nonresponders to intravenous therapy underwent direct-current cardioversion. Both responders to intravenous therapy and converters to sinus rhythm after direct-current cardioversion were followed for 6 months in a double-blind oral treatment period of propafenone 150 mg 3 times daily or matching placebo. Pharmacologic conversion to sinus rhythm was achieved in 29% of the patients taking propafenone and in 17% of patients taking placebo (p > or = 0.10). Subsequent direct-current cardioversion in nonresponders was equally successful (70%) in both groups (p > or = 0.10). The proportion of patients free from recurrent symptomatic arrhythmia at 6 months was 67% for the propafenone and 35% for the placebo group (p < 0.01). Time to atrial fibrillation relapse was more favorable with propafenone than with placebo (p < 0.001). The incidence of drug-related side effects was 10% in the propafenone group and 14% in the placebo group. Thus, "slow" infusion of propafenone seems to be of limited value for terminating atrial fibrillation. Oral propafenone at a low dosage 150 mg 3 times daily is well tolerated and effective in maintaining sinus rhythm for 6 months after pharmacologic or electrical restoration of sinus rhythm.