Background: Amiodarone (AMIO) is for many years effectively used to control ventricular rate during atrial fibrillation (AF) and to convert it into sinus rhythm. However, due to its delayed onset of action, ranolazine (RAN), a new antianginal agent with atrial-selective electrophysiologic properties, has recently been attempted as add-on therapy with AMIO to facilitate AF conversion. Methods: To establish the role of this combination therapy, we enrolled 173 consecutive patients (68 +/- 10 years, 54% male) with recent-onset (< 48-hour duration) AF who were eligible for pharmacologic cardioversion. Patients were randomized to intravenous AMIO (loading dose 5 mg/kg in 1 hour followed by 50 mg/h; n = 81), or AMIO plus a single oral dose of RAN 1 g (n = 92). Results: Mean left atrial diameter did not significantly differ between groups, AMIO and AMIO + RAN (4.2 +/- 0.5 cm vs 4.1 +/- 0.4 cm, P = 0.18). The AMIO + RAN group compared with the AMIO-only group showed significantly shorter time to conversion (8.6 +/- 2.8 hours vs 19.4 +/- 4.4 hours, P < 0.0001) and higher conversion rate at 24 hours (98% vs 58%, P < 0.001). Left ventricular ejection fraction did not markedly vary between the two groups and ranged within moderately reduced values. No serious clinically evident adverse effects were observed in any of the patients receiving either AMIO or the combination treatment. Conclusions: Our data demonstrate faster sinus rhythm restoration and enhanced conversion rate of AF after AMIO plus RAN in patients with preserved ejection fraction and left atrial size, implicating a synergistic effect of the two agents.