Background: Vascular endothelial growth factor (VEGF) is a key regulator of cardiac angiogenesis and is required for preventing decompensated heart failure. Soluble VEGF receptor-2 (sVEGFR-2) acts as an endogenous inhibitor of VEGF. Recently, we demonstrated that serum sVEGFR-2 levels are increased in proportion to insulin resistance among subjects with metabolic syndrome. However, the significance of sVEGFR-2 levels in patients with chronic heart failure (CHF) is unknown. Methods and results: We performed a prospective cohort study involving 117 symptomatic patients with CHF. Patients were followed up over 2 years. The primary outcome was major adverse cardiac events (MACEs) defined as cardiovascular mortality, hospitalization due to congestive heart failure, acute coronary syndrome, stroke, and coronary revascularization. Serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), VEGF, and sVEGFR-2 were determined employing specific enzyme-linked immunosorbent assays. Patients were divided into two groups based on the optimal cut-off value of each biomarker determined by receiver operating characteristic curve (ROC) analyses. The median follow-up was 142 (IQR: 39-381) days. MACEs developed in a total of 52 patients (44%). In Kaplan-Meier analyses, high-NT-proBNP and high-sVEGFR-2, but not high-VEGF, were significantly correlated with MACEs (P = 0.002, P = 0.007, P = 0.2, by log-rank test, respectively). Cox proportional hazard ratios (95% confidence interval) of high-NT-proBNP, high-sVEGFR-2, and high-VEGF were 2.5 (1.4-4.3), 2.4 (1.2-4.5), and 1.8 (0.7-4.2), respectively. Even in stepwise multivariate Cox proportional hazard analysis, high-sVEGFR-2 was an independent predictor of MACEs. Time-dependent survival ROC analyses revealed that the area under the curve of NT-proBNP, sVEGFR-2, and the combination of both were 0.61, 0.66, and 0.70 at 90 days, and 0.67, 0.66, and 0.71 at 270 days, respectively. These findings indicate that the combination of NT-proBNP and sVEGFR-2 is superior to NT-proBNP or sVEGFR-2 alone to predict MACEs. Conclusions: The present study has first demonstrated that sVEGFR-2 serves as an independent and incremental predictor of MACEs in combination with NT-proBNP among patients with CHF.