INTRODUCTION: New defibrillation techniques are often compared to standard approaches using the defibrillation threshold. However, inference from thresholding data necessitates extrapolation from reactions to relatively ineffective shocks, an error prone procedure requiring large sample sizes for hypothesis testing and large safety margins for defibrillator implantation. In contrast, this article presents a clinically validated statistical model of a minimum error, four-shock defibrillation testing protocol for estimating the 80% effective defibrillation strength for a given patient (ED80). METHODS AND RESULTS: A Bayesian statistical model was constructed assuming that the defibrillation dose-response curve is sigmoidal, and the ED80 is between 150 and 750 V. The model was used to design a minimum predicted error testing protocol and estimates. To prospectively validate the testing protocol and estimates, 170 patients received voltage-programmed biphasic testing. Four fibrillation episodes were induced and terminated in each patient according to the Bayesian up-down protocol. In addition, a validation attempt was made at the estimated ED80 rounded up to the nearest 50 V. In order to estimate the safety margin, in 136 patients, a defibrillation attempt was made at the rounded ED80 + 100 V. Of the 170 attempts at the rounded ED80, 143 (84%) attempts terminated fibrillation. Of the 136 attempts at the rounded ED80 + 100 V, 133 (98%) were effective. CONCLUSIONS: The four-shock Bayesian up-down protocol is the first clinical protocol to accurately predict an ED80 voltage. A 100 V increment above the ED80 provides an adequate safety margin. This simple and accurate method for estimating a highly effective defibrillation dose may be a valuable tool for population-based clinical hypothesis testing, as well as defibrillator implantation.