Sudden death in Wolff-Parkinson-White syndrome (WPW) is related to a very fast ventricular response to spontaneous atrial fibrillation (AF) conducted via accessory pathway (AP). The effect of oral amiodarone was studied in 12 patients with WPW syndrome and life-threatening rapid ventricular response via an AP during spontaneous AF. The effective refractory period of the AP in the anterograde direction was 280 ms or less during control study in all patients. After amiodarone therapy, the effective refractory period remained 280 ms or less in 7 of the 12 patients. During incremental atrial pacing, the longest atrial pacing cycle length that produced block over an AP ranged from 200 to 310 ms (mean 261 +/- 42) during the control period and 240 to 980 ms (mean 377 +/- 198) after amiodarone therapy. During AF the shortest ventricular response via the AP could be measured in 10 of 12 of the patients both before and after amiodarone treatment and ranged from 200 to 290 ms (234 +/- 30) and 250 to 500 (mean 302 +/- 75), respectively (p less than 0.01). The average RR interval during AF before and after the drug ranged from 200 to 390 ms (mean 280 +/- 55) and 280 to 650 ms (mean 396 +/- 116), respectively (p less than 0.01). Thus, the safety of amiodarone in the WPW syndrome should be established by electrophysiologic studies and induction of AF, because amiodarone is not protective in all patients with WPW.