The gap junction modifier Rotigaptide (ZP123), which promotes cellular coupling, was hypothesized to decrease defibrillation thresholds during prolonged ventricular fibrillation (VF). Thirty-two New Zealand white rabbits were randomized to receive saline (control, n = 16) or Rotigaptide (n = 16). Following 4 min of untreated VF, biphasic defibrillation shocks were applied through chest wall patches, starting either at 300 volts (V) (n = 16) or 500 V (n = 16), with 200 V increasing steps to 900 V in case of shock failure. Rotigaptide significantly decreased defibrillation voltage requirements (average cumulative voltage of all shocks: 1206 +/- 709 V in control group vs. 844 +/- 546 V in treated group, P = .002). Rotigaptide had no effect on heart rate, QRS duration, QT interval, ventricular effective refractory period, monophasic action potential duration or on connexin 43 density using immunofluorescence. Rotigaptide improves the ability to defibrillate after untreated VF.