The ventricular rate during rapid atrial rhythms is related in Wolff-Parkinson-White (WPW) syndrome to antegrade effective refractory period of the accessory pathways. Among the many antiarrhythmic drugs available, amiodarone is most commonly used for its large therapeutic window and very long half-life. We report a case of cardiac pre-excitation syndrome in a young male patient in whom amiodarone therapy (3000 mg/weekly) was instituted to modify the dangerous ventricular response during atrial fibrillation (shortest R-R interval 190 ms, ventricular rate 210 beats/min). Four months later, starting pharmacological treatment, a new electrophysiological study documented a malignant ventricular arrhythmia: during atrial fibrillation the minimum R-R interval was 160 ms and the ventricular rate 280 beats/min. Finally, the possible mechanism of paradoxical effect observed in our patient is hypothesized. Amiodarone could favor conduction over the accessory pathways by slowing or blocking conduction into the atrioventricular node and decreasing concealed retrograde conduction into the accessory bypass tract by normally conducted beats.