The atrial fibrillation (AF) recurrence rate after pulmonary vein isolation (PVI) has been relatively high and in some unsuccessful PVI cases, antiarrhythmic drugs that were ineffective before PVI may become effective (hybrid therapy). The purpose of this study was to investigate the relationship between the brain natriuretic peptide (BNP) level and the effect of the hybrid therapy. In 28 lone AF patients undergoing hybrid therapy, the plasma BNP level was measured before PVI and before and 3 months after administering an antiarrhythmic drug. Fifteen patients were free of AF after the hybrid therapy (effective group), and 13 still had recurrent AF after (noneffective group). At baseline, in all patients the BNP level was elevated, and there were no significant differences in the BNP level between the 2 groups. The BNP level was significantly decreased after PVI in the effective group (56.8 ± 23.1 versus 37.5 ± 16.7 pg/mL, P < 0.05) but not in the noneffective group (74.3 ± 47.8 versus 79.7 ± 54.4 pg/mL, NS). The elevated BNP level normalized in all effective group patients. The criterion consisting of a net value of < 60.0 pg/mL or a reduction in the BNP level of > 10.0 pg/mL after PVI predicted the effective group patients with a high accuracy. A significant reduction in the BNP level after PVI may be a useful predictor of the responders to antiarrhythmic drug therapy in patients with recurrent AF after PVI. The hybrid therapy may be effective in patients whose PVs serve as a dominant AF substrate.