The mechanisms responsible for malignant ventricular arrhythmias associated with reperfusion of ischemic myocardium were delineated with a computerized, three-dimensional mapping system, with simultaneous eight-level transmural recordings from 232 bipolar sites. In six chloralose-anesthetized cats, regional ischemia was induced for 10 min by occlusion of the left anterior descending coronary artery, followed by reperfusion. At 10 min after ischemia, just before reperfusion, total ventricular activation time during sinus rhythm was significantly delayed (63 ± 8 vs 25 ± 2 msec before ischemia, p < .001). Ventricular tachycardia (VT) occurred within 15 sec after reperfusion and in three animals culminated in ventricular fibrillation. In 75% of cases of nonsustained VT, initiation occurred in the subendocardium, at the border of the reperfused zone via a mechanism not involving reentry, as determined by the fact that continuous activation was not apparent and the time from the end of the sinus beat to the beginning of VT (142 ± 14 msec) was not associated with any intervening depolarizations. In the remaining 25% of cases of nonsustained VT, initiation of the VT resulted from intramural reentry in the subendocardium adjacent to the site of delayed midmyocardial activation from the preceding sinus beat (total activation time = 151 ± 9 msec, p < .001 vs just before reperfusion). This reentrant mechanism was similar to that responsible for the majority of cases of VT during ischemia without reperfusion. Maintenance of VT during reperfusion occurred by nonreentrant mechanisms as well as by intramural reentry, with most cases of VT involving both mechanisms. Ventricular tachycardia leading to ventricular fibrillation was initiated in the subendocardium at the border of the reperfused zone by a nonreentrant mechanism and was maintained by both nonreentrant and reentrant mechanisms, at times in combination in the same beat. The coupling interval of the first ectopic beat of VT leading to ventricular fibrillation was not significantly different from that of nonsustained VT (199 ± 16 vs 189 ± 9 msec, p = NS). However, during the transition from VT to ventricular fibrillation, nonreentrant mechanisms arising both in the subendocardium and subepicardium led to very rapid acceleration of the tachycardia to the coupling interval of 92 ± 2 msec, resulting in enhanced functional block and further conduction delay, with the total activation time of the transition beats exceeding the coupling interval of the tachycardia. This subsequently led to the development of multiple small reentrant circuits and multiple simultaneous wavefronts characteristic of ventricular fibrillation. In the cases of nonsustained VT, none demonstrated nonreentrant activation in the epicardium or a cycle length less than 120 msec. Likewise, no rapid nonreentrant activation of the endocardium or development of ventricular fibrillation was demonstrated. Thus, VT during reperfusion of ischemic myocardium is most commonly initiated by a nonreentrant mechanism, although intramural reentry can contribute. Ventricular fibrillation occurs through a rapid nonreentrant acceleration of the tachycardia. The nature of this nonreentrant excitation remains to be elucidated, but may involve an abnormal form of automaticity or triggered activity.