Atrial Fibrillation (AF) is often initiated by pulmonary vein (PV) depolarizations. However, sustained PV firing (PVF) is infrequently observed in this population and has not been characterized. In 15 patients undergoing AF ablation we report the response of sustained PVF to pacing and pharmacological maneuvers. Sustained PVF was defined as discrete, repetitive, electrical activity during sinus rhythm that did not correspond with other electrical events (P, QRS, T wave), persisting > or =5 minutes and recorded at/or distal to PV ostium prior to ablation. During sustained PVF, pacing was performed from coronary sinus and/or posterior right atrium at different cycle lengths (900 to 400 ms; duration: 30 to 60 s) following which, if PVF persisted, in random order, isoproterenol and adenosine were administered and carotid sinus massage (CSM) was performed. PVF response was classified as: suppressed (complete quiescence), augmented (increase in frequency of PVF/AF initiation) and "no effect." Sustained PVF was observed in 16 veins. In 13 (81%) patients, PVF was suppressed during overdrive pacing with early recurrence (< or =5 s) postpacing regardless of pacing cycle length in 11 (85%) patients. PVF was augmented by isoproterenol in the majority of patients (88%) and showed mixed response to adenosine (augmented 40%, suppressed 20%, and no effect 40%). CSM appeared to have no effect on PVF in the majority of patients (86%). Sustained PVF is seen infrequently in patients undergoing AF ablation. Its response to pacing maneuvers argues against sustained reentry and supports triggered activity and/or abnormal automaticity as the mechanisms underlying the phenomenon.