Persistent atrial fibrillation (AF) is characterized by electrical remodeling, ie, marked decreases in the atrial effective refractory period (ERP), ERP rate adaptation, and atrial conduction velocity. Little information is available on the effects of class III antiarrhythmic drugs on the remodeled atrium. We studied the effects of the class III antiarrhythmic drugs nifekalant, ibutilide, and amiodarone on rate-dependent changes in atrial action potential duration in patients with persistent AF. Right atrial (RA) monophasic action potential duration (MAPD) and intra-atrial conduction time (IACT) were measured at pacing cycle lengths (CLs) of 800, 700, 600, 500, 400, 350, 300, and 250 ms before and after administration of nifekalant (0.4 mg/kg + 0.3 mg/kg/hr, iv), amiodarone (5 mg/kg, iv), or ibutilide (0.01 mg/kg, iv) in 31 patients after successful internal cardioversion of chronic AF of > 2 months duration. Nifekalant and ibutilide significantly increased RA MAPD and the ERP at each CL in a reverse rate-dependent manner. Amiodarone did not affect RA MAPD. Nifekalant did not affect IACT, whereas amiodarone increased IACT at each CL in a rate-dependent manner, and ibutilide increased IACT at CLs ≤ 350 ms. The atrial electrophysiologic effects of the class III antiarrhythmic drugs nifekalant, amiodarone, and ibutilide differ, depending on the degree of electrical and structural remodeling and the effects of the drugs on the depolarizing and repolarizing currents.