Objectives: The aim of this study was to determine whether left ventricular ejection fraction (LVEF) influences the relationship between abnormal myocardial sympathetic innervation imaging by iodine 123 meta- iodobenzylguanidine (123I-mIBG) and outcomes in patients with heart failure (HF). Background: In systolic HF, both abnormal 123I-mIBG imaging and reduced LVEF are associated with higher risk of cardiovascular events. Whether 123I-mIBG imaging has the same predictive value across the LVEF spectrum is unclear. Methods: Among 985 patients in the ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) trial with New York Heart Association functional class II or III HF and site-reported LVEF ≤35%, the core laboratory-determined LVEFs were available for 901 subjects, ranging from 20% to 58% (mean LVEF 34 ± 7%), and was >35% in 386 subjects. Results: The mean age of the study population was 62 ± 12 years, 80% were male, and the majority had New York Heart Association functional class II symptoms and HF of nonischemic etiology. At all levels of LVEF, the 123I-mIBG heart-to-mediastinum ratio of <1.6 was associated with a higher risk of death or potentially lethal arrhythmic event and of the composite of cardiovascular death, arrhythmic event, and HF progression. Comparing subjects with LVEF ≤35% and >35%, there was no evidence of effect modification of LVEF on the risk associated with low heart-to-mediastinum ratio for death or arrhythmic event (adjusted hazard ratio: 2.39 [95% confidence interval (CI): 1.03 to 5.55] vs. 5.28 [95% CI: 1.21 to 23.02]; interaction p = 0.48) and for the composite (adjusted hazard ratio: 1.80 [95% CI: 1.01 to 3.23] vs. 2.41 [95% CI: 1.11 to 5.23]; interaction; p = 0.86). For death or arrhythmic event, the heart-to-mediastinum ratio appeared to improve the risk discrimination beyond clinical and biomarker data among both LVEF groups, with improvement in the model C-statistic (0.67 vs. 0.69, p = 0.03) and integrated discrimination improvement (p = 0.0008). Conclusions: 123I-mIBG imaging has prognostic value across a spectrum of LVEFs. Further studies may be warranted to prospectively test the prognostic value of 123I-mIBG imaging in patients with HF and an LVEF >35%. © 2012 American College of Cardiology Foundation.