Little is known about the effects of cardiac preload and cardiac geometry on defibrillation efficacy with endocardial electrodes. We studied nine pigs implanted with an endocardial lead system in the normal and reduced preload state. In the reduced preload state, a balloon catheter was inflated in the inferior vena cava (IVC) for 20 seconds prior to the induction of ventricular fibrillation (VF). Complete occlusion of the IVC and reductions in preload were confirmed by observing deformation of the contrast-filled balloon, a reduction in cardiac size by fluoroscopy, and reductions in ventricular pressures. Biphasic shocks were delivered after 10 seconds of VF using a recursive up-down protocol. VF was induced 20 times for each preload state, and the 50% effective doses (ED50) for energy, current, and voltage were estimated by averaging all shocks for that state. At reduced preloads, energy decreased from 12.1 ± 3.0 J (±SD) to 10.5 ± 2.9 J (p < 0.01), voltage decreased from 415 ± 51 V to 390 ± 51 V (p < 0.05), and current decreased from 8.6 ± 1.5 A to 7.6 ± 1.5 A (p < 0.01), while impedance rose from 49.2 ± 3.8 X to 52.8 ± 4.4 X (p < 0.001). We conclude that reducing cardiac preload and cardiac size significantly lowers ED50 defibrillation energy, current, and voltage. This outcome may be caused directly by the decrease in blood volume as evidenced by increased impedance and/or may be due to changes in heart geometry and stretch.