Although it is generally assumed that defibrillation becomes more difficult when the duration of VF is prolonged, after a failed defibrillation attempt, there is little information on the defibrillation efficacy of multiple shocks delivered at the same energy. The purpose of this study was to systematically examine the efficacy of a second shock delivered at the same or reversed polarity after a failed first shock. Defibrillation was attempted after 10 seconds of VF in 12 pigs (30-56 kg) using biphasic waveforms and a nonthoracotomy lead system. Shock energy was held constant for the first and second shocks at 50%-90% of the DFT. The second shock was delivered 10 seconds after a failed first shock. First and second shock polarity (first phase) was randomized to (+, +), (+, -), (-, -), (-, +). The incidence of successful defibrillation (for all polarities) was 12.3% for first and 49.1% for second shocks (P < 0.0001). Anodal first shocks had a 17.2% incidence of success as opposed to a 7.4% incidence of success with cathodal first shocks (P = 0.001). Anodal second shocks had a 55.5% incidence of success compared to a 42.7% incidence of success with cathodal second shocks (P = 0.008). There was no significant benefit from polarity reversal after a failed first shock (P = 0.29). In conclusion, less energy is required for successful defibrillation by a second shock after a failed first. The optimal configuration for first and second shocks is with the RV as anode. Polarity reversal of a second shock after a failed first does not affect the probability of second shock success.