Background: Earliest postshock activation following failed defibrillation shocks slightly lower than the defibrillation threshold (DFT) in large animals appears to arise from a focus. We tested the hypothesis that these foci are caused by early or delayed afterdepolarizations (EADs or DADs) by performing epicardial electrical mapping and giving the EAD inhibitor pinacidil or the DAD inhibitor flunarizine to see if the foci were extinguished or altered in timing or location. Methods and Results: A sock containing 504 electrodes was placed over the entire ventricular epicardium of 12 open-chested pigs. After the DFT was determined and additional shocks given, pinacidil was administered to 6 pigs and flunarizine to 6 pigs. Then, the DFT was again determined and additional shocks were given. Pinacidil significantly shortened the effective refractory period (ERP) (162 ± 16 vs 130 ± 28 msec) and action potential duration (APD90) (179 ± 6 vs 149 ± 19 msec) and significantly increased the peak frequency of the power spectrum of a left ventricle (LV) electrode during ventricular fibrillation (VF) (9.3 ± 0.6 vs 10.5 ± 1.0 Hz), while flunarizine did not significantly alter the ERP (162 ± 8 vs 167 ± 18 msec) or APD90 (187 ± 12 vs 191 ± 20) but significantly reduced the peak frequency (9.2 ± 0.5 vs 7.5 ± 1.0 Hz). These findings suggest the drugs had their expected electrophysiological effects. However, the DFT was not significantly changed by either drug. Following the same strength shock 10% below the predrug DFT, earliest postshock activation arose in a focal epicardial pattern from the anterior-apical LV both before and after the drugs. The time from the shock until the appearance of this activation was not significantly different before and after either drug. Conclusion: The lack of change in DFT as well as the lack of change in the incidence, location, and timing of the postshock focus with sub-DFT strength shocks before and after pinacidil and flunarizine provide evidence that these foci are not caused by triggered activity.