Oscillations in T-wave morphology, particularly T-wave alternans (TWA), have been fundamentally linked to increased susceptibility to ventricular fibrillation (VF). We tested the hypothesis that the escalation in complexity of T-wave oscillations prior to VF is attributable to increased spatial heterogeneity of repolarization. Peak spatial T-wave heterogeneity (TWH) was measured by second central moment analysis of T-wave morphology in electrograms from a 4-electrode epicardial plaque in 12 chloralose-anesthetized dogs during occlusion of the left anterior descending coronary artery. TWH differentiated cases in which myocardial ischemia provoked VF from those without VF (563±56 vs 139±36 µV, p<0.01). The increase in TWH began at 2.25 min after the start of occlusion and continued until VF occurred at 4.36±0.14 min. Heightened TWH was associated with TWA (155±19µV), T-wave multupling (at 386±100µV), complex oscillatory T-wave forms (at 560±76µV), and discordant TWA episodes (at 572±98µV) (each p<0.05 above preocclusion baseline of 70±8µV). Interlead TWH in precordial ECGs in 12 closed-chest anesthetized pigs during angioplasty-balloon induced myocardial ischemia also discriminated between animals that experienced VF (from 90±14 at baseline to 382±39µV, p<0.05) compared with those without VF (from 96±17 at baseline to 199±61µV, NS). Ischemia-induced changes in ST-segment and T-wave amplitude did not predict VF. CONCLUSION: Heightened spatial heterogeneity of repolarization, as assessed by second central moment analysis of TWH, underlies the progression from elevated TWA to more complex T-wave patterns and increased risk for ischemia-induced VF. Monitoring spatial TWH from precordial leads could prove useful in stratifying risk for life-threatening arrhythmias.