Antiarrhythmic drugs are commonly used with the implantable cardioverter/defibrillator to treat recurrent ventricular tachyarrhythmias. Since various antiarrhythmic drugs have been reported to alter defibrillation threshold, an important question is whether the device will provide adequate energy for defibrillation during long-term follow-up and to what extent antiarrhythmic drug treatment will affect defibrillation energy requirements. To answer these questions, the defibrillation thresholds were determined in 20 patients using an epicardial patch-patch lead configuration at the time of implantation and at the time of pulse generator replacement. During a mean follow-up period of 24 +/- 6 months, the defibrillation threshold increased significantly from 14.2 +/- 3.7 joules to 18.3 +/- 5.5 joules in the entire group (P < 0.05). This increase in defibrillation threshold was due to a marked elevation of defibrillation energy requirements in the subgroup of patients taking amiodarone compared with patients receiving mexiletine. Based on these results it is mandatory to retest defibrillation threshold at any time of pulse generator replacement to guarantee continued effectiveness. In particular, if amiodarone treatment is initiated after implantation of a defibrillator, it is recommended to reevaluate defibrillation threshold to ensure an adequate margin of safety.