Background: While reentry within the ventricular myocardium (VM) is responsible for the maintenance of short-duration ventricular fibrillation (SDVF; VF duration <1 minute), Purkinje fibers (PFs) are important in the maintenance of long-duration ventricular fibrillation (LDVF; VF duration >1 minute). Objective: The purpose of this study was to test the hypothesis that the mechanisms of defibrillation may also be different for SDVF and LDVF. Methods: A multielectrode basket catheter was deployed in the left ventricle of eight beagles. External defibrillation shocks were delivered with a ramp-up protocol after SDVF (20 seconds) and LDVF (150 seconds). Earliest VM and PF activations were identified after the highest energy shock that failed to terminate VF and the successful shock. Results: Defibrillation was successful after 36 ± 12 and 181 ± 14 seconds for SDVF and LDVF, respectively. The time after shock delivery until earliest activation was detected for failed shocks and was significantly longer after LDVF (138.7 ± 24.1 ms) than after SDVF (75.6 ± 8.7 ms). Earliest postshock activation after SDVF typically initiated in the VM (14 of 16 episodes), while it always initiated in the PF (16 of 16 episodes) after LDVF. Sites of earliest activity during sinus rhythm correlated with sites of earliest postshock activation for PF-led cycles but not for VM-led cycles. Conclusion: Earliest recorded postshock activation is in the Purkinje system after LDVF but not after SDVF. This difference raises the possibility that the optimal defibrillation strategy is different for SDVF and LDVF. © 2010 Heart Rhythm Society.