The objective of this randomized, double-blind, placebo-controlled clinical trial was to test the efficacy and safety of a new sustained-release preparation of the antiarrhythmic drug propafenone (propafenone SR) in reducing the frequency of symptomatic arrhythmia recurrences in patients with atrial fibrillation (AF). Patients with a history of symptomatic AF who were in sinus rhythm were randomly assigned to receive placebo or propafenone SR 425, 325, or 225 mg, all twice daily. Recurrent symptomatic arrhythmias were documented using transtelephone electrocardiographic monitoring. Electrocardiograms were reviewed by an event committee that was blinded to treatment assignment. In the primary efficacy analysis, propafenone SR significantly lengthened the time to first symptomatic atrial arrhythmia recurrence at all 3 doses compared with placebo as assessed by log-rank test: propafenone SR 425 mg twice daily versus placebo twice daily, p <0.001; 325 mg twice daily versus placebo twice daily, p <0.001; and 225 mg twice daily versus placebo twice daily, p = 0.014. The median time to recurrence was 41 days in the placebo twice daily group, >300 days in the propafenone SR 425-mg group, 291 days in the 325-mg group, and 112 days in the 225-mg group. Adverse effects leading to withdrawal were higher in the propafenone SR 425-mg twice daily group than in any other group. Thus, propafenone SR has important and statistically significant antiarrhythmic effects in patients with AF.