BACKGROUND Wenxin Keli is a Chinese herb extract reported to be of benefit in the treatment of cardiac arrhythmias, cardiac inflammation and heart failure. METHODS AND RESULTS We evaluated the electrophysiologic effects of Wenxin Keli in isolated canine arterially-perfused right atrial preparations with a rim of right ventricular tissue (n=11). Transmembrane action potentials and a pseudo-electrocardiogram were simultaneously recorded. Acetylcholine (ACh, 1 μM) was used to induce atrial fibrillation (AF) and to test the anti-AF potential of Wenxin Keli (5 g/L). Wenxin Keli produced preferential abbreviation of action potential duration (APD90) in atria, but caused atrial-selective prolongation of effective refractory period, due to development of post-repolarization refractoriness. The maximum rate of rise of the action potential upstroke (Vmax) was preferentially reduced in atria. Diastolic threshold of excitation increased in both atria and ventricles, but much more in atria. The duration of the “P wave” (index of atrial conduction time) was prolonged to a much greater extent than the duration of the “QRS complex” (index of ventricular conduction time). Wenxin Keli significantly reduced INa and shifted steady-state inactivation to more negative potentials in HEK293 cells stably expressing SCN5A. Wenxin Keli prevented induction of persistent AF in 100% atria (6/6) and, in another experimental series was found to terminate persistent ACh-mediated AF in 100% of atria (3/3). CONCLUSION Wenxin Keli produces atrial-selective depression of INa-dependent parameters in canine isolated coronary perfused preparations via a unique mechanism and is effective in suppressing AF and preventing its induction, with minimal effects on ventricular electrophysiology.