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Introduction: The specific waveform providing optimal defibrillation threshold (DFT) is unknown. We compared the defibrillation efficacy of biphasic pulses with second phases (P2) of 2 and 5 msec in a randomized prospective clinical study., Methods and Results: Intraoperative DFTs of 62 patients (age 54 +/- 13 years; ejection fraction 43% +/- 17%; amiodarone 47%, d,l-sotalol 13%) were determined in random order using a binary search protocol. Anodal shocks of 60% tilt first phases (P1) and P2 of 2 msec/5 msec were delivered from two 100-microF capacitors between the right ventricular electrode and the test housing of a Phylax 06/XM device. Mean DFT was significantly lower using the shorter P2 (9.5 +/- 4.5 J vs 11.3 +/- 5.2 J; P < 0.0001). According to subgroup analysis, the effect of changing P2 duration was only influenced by antiarrhythmic treatment. DFT decreased markedly using the shorter P2 in patients treated with amiodarone (10.7 +/- 4.9 J vs 13.4 +/- 5.6 J; P < 0.00001) or d,l-sotalol (6.1 +/- 3.3 J vs 9.1 +/- 4.6 J; P < 0.05). The difference in patients not treated with Class III drugs was found to be insignificant. Chronic amiodarone treatment increased DFT only when the longer P2 was used., Conclusion: Biphasic shocks with shorter P2 should be used in patients undergoing Class III antiarrhythmic treatment.