Background —A previous retrospective study by our group suggested that shocks timed to the upslope of the shocking lead electrogram improved defibrillation efficacy. The goal of this study was to prospectively determine whether defibrillation threshold could be reduced by use of an algorithm that timed shocks to the upslope of coarse ventricular fibrillation (test treatment) compared with shocks delivered asynchronously after 10 seconds of fibrillation (control treatment). Methods and Results —Ten pigs were instrumented with a 3-lead system for internal defibrillation. Initial estimates of the energy required to achieve defibrillation E 50 for both treatments were made by an up/down method. Subsequently, additional shocks at V 50 ±10% and V 50 ±20% were given for each treatment to obtain data points at higher and lower intensities. Probability-of-success curves were estimated for both treatments by the best-fit method. Energies required were significantly lower for the timed shocks than for the asynchronous shocks ( P <0.001). E 80 was reduced 15.5%, from 27.1±2.5 to 22.9±1.8 J ( P <0.002). The width of the probability-of-success curve (E 80 −E 20 ) for the test treatment was also significantly narrower than that for the control treatment (7.1±0.9 versus 10.8±1.7, P <0.01). Normalized curve width (E 80 −E 20 )/E 50 was decreased from 51±5% of E 50 for control shocks to 37±4% of E 50 for synchronous shocks ( P <0.02). Conclusions —In this model, defibrillation threshold is lower and more deterministic when shocks are timed to the upslope of the shocking lead electrogram. If a similar reduction is observed in humans, shock timing may lower defibrillation threshold and simplify programming of shock intensity.