Oscillations in T-wave morphology, particularly T-wave alternans (TWA), have been fundamentally linked to increased susceptibility to ventricular fibrillation (VF). We investigated whether the escalation in complexity of T-wave oscillations before VF is attributable to increased spatial heterogeneity of repolarization. Peak interlead T-wave heterogeneity (TWH) was measured by second central moment analysis of T-wave morphology in epicardial electrograms in dogs during left anterior descending coronary artery occlusion. TWH differentiated cases in which myocardial ischemia provoked VF from those without VF (563 ± 56 vs. 139 ± 36 μV, P < 0.01). In the former group, progressive, significant increases in TWH above preocclusion baseline (70 ± 8 μV) began at 2.25 min after the start of occlusion and were associated successively with TWA (at 155 ± 19 μV), T-wave multupling (at 386 ± 100 μV), complex oscillatory T-wave forms (at 560 ± 76 μV), discordant TWA (at 572 ± 98 μV), and VF at 4.36 ± 0.14 min. TWH in precordial ECGs in 12 pigs during angioplasty-balloon-induced myocardial ischemia also discriminated animals that experienced VF (from 90 ± 14 at baseline to 382 ± 39 μV, P < 0.05) from those without VF (from 96 ± 17 at baseline to 199 ± 61 μV, NS). Ischemia-induced changes in ST segment and T-wave amplitude did not predict VF. Heightened spatial heterogeneity of repolarization, as assessed by second central moment analysis of TWH, underlies TWA and increased risk for ischemia-induced VF. Monitoring spatial TWH from precordial leads could prove useful in stratifying risk for life-threatening arrhythmias.