Implantable cardioverter-defibrillator (ICD) pulse generators are now routinely positioned in a pectoral location, either submuscularly (under the pectoralis muscles) or subcutaneously (over the pectoralis muscles). Furthermore, in current ICDs, the generator shield usually participates in the defibrillation energy pathway ("hot can"). Consequently, the precise generator location could affect defibrillation system efficacy. To assess this issue, we compared high voltage pathway impedance and defibrillation threshold (DFT) in 20 patients undergoing submuscular and 46 patients undergoing subcutaneous pectoral implantation of an Angeion Sentinel ICD and an AngeFlex dual-coil defibrillation lead. Measurements were performed at time of ICD implant, pre-hospital discharge, and 1, 3 and/or 6 months later. Following induction of ventricular fibrillation, 569 biphasic waveform shocks were delivered between the generator shield and either the distal defibrillation coil (RV/can configuration) or both proximal and distal coils (RV/SVC/can configuration). Impedance differences between submuscular and subcutaneous implants were approximately 3-4 Ohms (p value of 0.132 to < 0.001 depending on time of follow-up and lead configuration). A significant increase in impedance over time was noted independent of implant location and lead configuration. The DFT at implant or pre-discharge was assessed in 27 individuals, and was 9.9 +/- 3.8 J in 8 patients in the submuscular group, and 7.4 +/- 3.3 J in 19 patients in the subcutaneous group (p = 0.057). In conclusion, anatomic location of a "hot can" ICD generator (submuscular versus subcutaneous) influences impedance to defibrillation current, but the impact is of small magnitude and does not appear to result in clinically important differences in DFT.