BACKGROUND Few antiarrhythmic agents have been shown in randomized controlled trials to be effective and well tolerated in the prophylaxis of paroxysmal supraventricular tachycardia or paroxysmal atrial fibrillation. Propafenone, a class IC anti-arrhythmic agent with weak beta-adrenoceptor antagonist properties, has shown promise in preliminary clinical studies. RESULTS A double-blind, placebo-controlled trial of the efficacy and tolerability of propafenone was undertaken in 100 patients with paroxysmal supraventricular tachycardia ([PSVT] n = 52) or atrial fibrillation/flutter ([PAF] n = 48) who had recorded two or more symptomatic arrhythmia recurrences by transtelephonic ECG monitoring during a 3-month drug-free observation period. Patients were randomized into two consecutive crossover periods of propafenone (300 mg BID) versus placebo followed by 300 mg TID propafenone versus placebo. Analysis was based on the time to treatment failure, defined as the interval from treatment onset to the occurrence of either ECG-documented arrhythmia or an intolerable adverse event. With a proportional-hazards model, we determined the relative risk (95% confidence interval) of treatment failure after the achievement of steady-state drug levels for placebo compared with propafenone 300 mg BID to be 6.8 (2.2 to 21.2, P < .001, n = 45) for PSVT and 6.0 (1.8 to 20.0, P = .004, n = 30) for PAF. Due to a greater incidence of adverse events on high-dose propafenone, the relative risks of receiving placebo rather than propafenone 300 TID were only 2.2 (0.9 to 5.3, P = .1, n = 34) for PSVT and 1.9 (0.7 to 4.7, P = .2, n = 25) for PAF. However, if adverse events were excluded in the high-dose comparison, relative risks for arrhythmia recurrence were 15.0 (2.0 to 113, P = .009) for PSVT and incalculable (no preferences for placebo, P = .0002) for PAF. One episode of wide-complex tachycardia was documented during propafenone therapy. CONCLUSIONS Propafenone is of value in the prophylaxis of both PSVT and PAF. A dose of 300 mg BID is effective and well tolerated. A larger dose of 300 mg TID causes more adverse effects but may be more effective in those who can tolerate it.