Objectives: Fixed- and escalating-dose defibrillation protocols are both in clinical use. Clinical observations suggest that the probability of successful defibrillation is not constant across a population of patients with ventricular fibrillation (VF). Common animal models of electrically induced VF do not represent a clinical VF etiology or reproduce clinical heterogeneity in defibrillation probability. The authors hypothesized that a model of ischemically induced VF would exhibit heterogeneous defibrillation shock strength requirements and that an escalating-dose strategy would more effectively achieve prompt defibrillation. Methods:Forty-six swine were randomized to fixed, lower-energy (150 J) transthoracic shocks (group 1) or escalating, higher-energy (200 J–300 J–360 J) shocks (group 2). VF was induced by balloon occlusion of a coronary artery. After 1 or 5 minutes of VF, countershocks with a biphasic waveform were administered. The primary endpoint was successful defibrillation (termination of VF for 5 seconds) with ≤3 shocks. Results: VF was induced with occlusion or after reperfusion in 35 animals. Only five of 17 group 1 animals (29%, 95% CI = 10 to 56) could be defibrillated with ≤3 shocks; 15 of 18 group 2 animals (83%, 95% CI = 59 to 96) were defibrillated with ≤3 shocks (p < 0.002 vs. group 1). Nine of the group 1 animals (75%) that could not be defibrillated with 150-J shocks were rescued with ≤3 shocks ranging from 200 to 360 J. Conclusions: In this ischemic VF animal model, defibrillation shock strength requirements varied among individuals, and when defibrillation was difficult, an escalating-dose strategy was more effective for prompt defibrillation than fixed, lower-energy shocks.