Autonomic nervous system dysfunction is common in congestive heart failure (CHF) and is believed to predispose patients to an increased risk of death. This study aimed to assess the prognostic significance of heart rate variability (HRV) measurements in conjunction with scintigraphic imaging using metaiodobenzylguanidine (MIBG) labeled with iodine-123 (I-123-MIBG), which detects abnormalities in autonomic nervous activity, in patients with stable CHF during optimal medical treatment. The study population included 52 patients (56 +/- 12 years of age) with a mean left ventricular ejection fraction of 31 +/- 12%. All underwent I-123-MIBG scanning and 24-hour ambulatory electrocardiographic monitoring for the analysis of HRV on entrance into the study. The heart/mediastinum MIBG uptake ratio was calculated. HRV analysis included the assessment of time- and frequency-domain variables. During the 2-year follow-up, 14 patients (27%) died. MIBG uptake at 1 hour was less (1.39 +/- 0.10) in nonsurvivors than in survivors (1.50 +/- 0.16; p = 0.013). In univariate Cox regression analysis, MIBG uptake was a significant prognostic factor (p = 0.038, hazard ratio [HR] 0.017, 95% confidence interval [CI] 0.00 to 0.79). Time- and frequency-domain variables were similar in survivors and nonsurvivors. However, high-frequency power was associated with an increased risk for sudden death (HR 0.310, 95% CI 0.101 to 0.954, p = 0.041) but not with all-cause mortality. In conclusion, cardiac I-123-MIBG imaging identifies patients with CHF at high risk of dying and may be a more reliable predictor of overall mortality than HRV.