The duration of ventricular fibrillation (VF) that precedes a high energy shock has been recognized as a critical determinant of defibrillation outcome. Factors such as metabolic acidosis or alkalosis do not affect outcome. The authors hypothesized that release of myocardial adenosine during VF could potentially mediate the time-dependent effects of VF duration on defibrillation. Defibrillation threshold (DFT) was therefore determined in dogs during concurrent infusion of adenosine and dipyridamole (a nucleoside transport blocker). Transthoracic DFT increased by approximately 50%, whereas transmyocardial DFT increased by approximately 100% in a separate group of dogs. These effects of adenosine on DFT were abolished when the dogs were autonomically denervated, suggesting that the deleterious effects of adenosine on DFT are due to its antiadrenergic mechanism of action. These data indicate that adenosine release during VF can markedly increase DFT. Since adenosine myocardial release during VF is time dependent, it is likely that adenosine plays a significant role in mediating the increase in threshold that is dependent on the duration of VF.