To define the relationship between ischemia-reperfusion-induced myocardial damage (IRD) and the occurrence of ventricular tachycardia (VT) and fibrillation (VF), we studied 23 dogs with a three-dimensional activation mapping system. Left anterior descending (LAD) coronary artery occlusion and reperfusion were performed while recording electrograms during VF and atrial pacing. Prior nonischemic sites showing IRD, defined as at least 10% loss of electrogram voltage after reperfusion, had the longest ventricular effective refractory periods (ERPs). IRD sites also occurred more frequently in dogs with reperfusion VF (44 ± 2 sites, P < 0.01) compared with dogs with VT (18 ± 5 sites) and no VT (16 ± 3 sites). In dogs (n = 3) with 3 h of reperfusion, 95% of IRD sites still had lower voltage than those recorded during occlusion. Activation mapping of the first eight complexes of VF had Purkinje or endocardial focal origin in 57%, and complexes originated from IRD sites in 28%. In contrast, dogs with only reperfusion VT also had Purkinje or endocardial focal origin in 79%, but only 5% (P < 0.01 vs. VF dogs) of the sites of origin had IRD. Therefore, dogs with reperfusion VF had more IRD sites where the ERP was longest, and more focal ventricular complexes originated from IRD sites, indicating that IRD may be one important factor in the occurrence of VF during reperfusion.