Although both long QT syndrome (LQTS) and coronary occlusion/reperfusion (O/R) are arrhythmogenic, they affect ventricular action potential duration (APD) differently. In contrast to the prolonged APD in LQTS, ischemia abbreviates APD after a transient prolongation. Thus, we hypothesized that the dynamic interactive effects of ischemia and LQTS on APD and its dispersion would affect ventricular arrhythmogenicity. We mapped transmural distribution of action potentials in 6 groups of 10 isolated wedges of canine ventricular walls: LQTS-O/R, LQTS-only, and O/R-only, with separate groups for pacing cycle lengths (PCL) of 1,000 and 2,000 ms. We created type 3 LQTS with anemone toxin II (ATX-II), followed >30 minutes later by arterial occlusion (40 minutes) and reperfusion (>100 minutes). Arterial occlusion prolonged initially (first 4 minutes) and then shortened APD. Early afterdepolarizations (EADs) occurred during the initial 4 minutes of occlusion in 4 of the 10 (4/10) LQTS-O/R wedges at PCL of 2,000 ms, but not in the other groups. Reperfusion restored APD in the O/R-only groups but caused APD to overshoot its original duration, indicating depressed repolarization reserve, in the LQTS-O/R group. Reperfusion increased the dispersion of APDs and initiated ventricular tachycardia/fibrillation (VT/VF) in 7/10 and 6/10 of LQTS-O/R wedges, and in 2/10 and 1/10 of O/R-only wedges, at PCLs of 1,000 and 2,000 ms, respectively. The LQTS-only wedges had neither EADs nor VT. We conclude that coronary O/R increased the arrhythmogenicity of LQTS via cumulative prolongation of APD, increase in repolarization dispersion, and suppression of repolarization reserve.