Background: Heart failure (HF) involves both mechanical and autonomic nervous system dysfunction that can lead to sudden cardiac death. In the failing human heart, there is increased release of norepinephrine from neurons and reduced uptake. Iodine-123–labeled metaiodobenzylguanidine (123I-mIBG) demonstrates reduced global uptake and increased washout associated with increased mortality in HF. This research examined the potential benefits of single-photon emission computed tomography (SPECT) regional quantitation in risk stratification of HF patients and its role in prediction of cardiac morbidity and mortality. Methods: Twenty-two clinically diagnosed HF patients were recruited into this study. The subjects underwent myocardial perfusion SPECT and cardiac sympathetic imaging with 123I-mIBG. Early (at 15 min after injection) and delayed (four hours after injection) planar and SPECT were performed. Visual and semiquantitative analysis was conducted, and global (from planar imaging) and regional (from SPECT imaging) uptake and washout indices determined. The patients were clinically followed for up to two years, and the cardiac events (CEs) in these patients were recorded and correlated with the various parameters. Results: The occurrence of a CE in HF was independent of the patients' demographics or the cause of HF. Genetic biomarkers were unable to reliably predict CEs. Global or regional uptake had limited ability to predict a CE, whereas regional washout from the inferior wall (P = .005) was a statistically significant predictor of CEs. Similarly, a high washout of 40% or more from the peri-infarcted and noninfarcted segments on myocardial perfusion scintigraphy was also a significant predictor of CEs (P = .035). Conclusion: HF is a complex, multifactorial, progressive disease that appears to begin regionally. 123I-mIBG provides a valuable tool in imaging the global and regional sympathetic nervous system innervation of the heart. This may allow early identification and stratification of patients at risk of sudden cardiac death.