Background: Augmentation of sympathetic nerve activity (SNA) is one of the underlying pathphysiologies of cardiorenal syndrome (CRS). However, impact of augmented SNA on prognosis in CRS remains unknown. Objective: We examined whether change in cardiac SNA detectable by metaiodobenzylguanidine (MIBG) imaging predicts mortality in patients with CRS. Methods and Results: Cardiac SNA activity was quantified as heart-to-mediastinum ratio (HMR) of MIBG image in 280 patients (aged 61 ± 16 years, 73% male) with heart failure (26% ischemic etiology) and reduced left ventricular ejection fraction (<50%). Patients with end-stage renal disease were excluded, and those with estimated glomerular filtration rate of <60 ml/min/1.73m 2 were defined as patients with CRS. During 50 ± 35 months of follow-up, cardiac death occurred in 48 patients (83% heart failure, 17% sudden death). Compared with 113 non-CRS patients, 167 CRS patients were older and had higher prevalence of diabetes, lower ejection fraction, lower hemoglobin level and worse 5-year survival rate (87.4% vs. 75.6% p<0.01). In a Cox proportional hazards model, late HMR of <1.57 (hazard ratio for mortality (HR): 6.98; 95% confidence interval (CI) = 3.33-16.52; p<0.01) and 1 mg/dl decrease in hemoglobin level (HR: 1.29; 95% CI =1.08-1.53; p<0.01) had significant predictive values, though CRS alone did not (HR: 1.57; 95% CI=0.81-3.25; p=0.18). Prognosis of CRS patients with late HMR of ≥1.57 was comparable to that of non-CRS patients (Figure 1). In CRS patients with late HMR of <1.57, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) (HR: 0.29; 95% CI=0.12-0.67; p<0.01) and β−blocker (HR: 0.38; 95% CI=0.17-0.82; p=0.01) were associated with better prognosis (Figure 2). Conclusions: Assessment of cardiac SNA by MIBG activity can identify high-risk patients among CRS patients. Current ACEI/ARB and β-blocker therapies appear to improve prognosis of those high-risk patients as well.