Background Pulmonary vein (PV) isolation is commonly performed in patients with drug-refractory atrial fibrillation (AF) and in cases of unsuccessful ablation, antiarrhythmic agents that were ineffective before the ablation sometimes become effective afterward. Therefore, the effects and mechanisms of hybrid therapy with pilsicainide and PV isolation for AF were assessed in the present study. Methods and Results Seventy-four patients with paroxysmal AF in whom pilsicainide was ineffective underwent PV isolation. If AF recurred, a second procedure was performed and if AF recurred again, pilsicainide was re-administered. After the first procedure, AF recurred in 42 patients, and a second procedure was performed in 31 patients, of whom 28 had recovery of left atrial (LA)-PV conduction and non-PV foci were identified in 3. After the second session, ablation eliminated AF without drugs in 53 (72%) patients. Pilsicainide suppressed the conduction properties at the LA-PV junction. In 21 patients with recurrence of AF, pilsicainide was re-administered and eliminated AF in 11 patients (success with pilsicainide: 86%). Conclusions In cases of unsuccessful PV isolation, pilsicainide may prevent AF by modifying the LA-PV conduction properties. Hybrid therapy with pilsicainide and PV isolation may be an effective therapeutic approach for AF. (Circ J 2005; 69: 1503 - 1507)