Introduction: Two published studies reported natriuretic peptides can aid in risk-stratification of Emergency Department (ED) syncope. We sought to assess the role of N-Terminal pro Brain Natriuretic Peptide (NT pro-BNP) to identify syncope patients at risk for serious adverse events (SAE) within 30 days of the ED visit, and its value above that of the Canadian Syncope Risk Score (CSRS). Methods: We conducted a multicenter prospective cohort study at 6 large Canadian EDs from Nov 2011 to Feb 2015. We enrolled adults who presented within 24-hours of syncope and excluded those with persistent altered mentation, obvious seizure, and intoxication. We collected patient characteristics, nine CSRS predictors (includes troponin), ED management and NT pro-BNP levels. Adjudicated serious adverse events (SAE) included death, cardiac SAE (arrhythmias, myocardial infarction, serious structural heart disease) and non-cardiac SAE (pulmonary embolism, severe hemorrhage and procedural interventions within 30-days). We used two tailed t-test and logistic regression analysis. Results: Of the 1359 patients (mean age 57.2 years, 54.7% females, 13.3% hospitalized) enrolled, 148 patients (10.9%; 0.7% deaths, 7.9% cardiac SAE including 6.1% arrhythmia) suffered SAE within 30-days. The mean NT pro-BNP values, when compared to the patients with no SAE (499.8ng/L) was significantly higher among the 56 patients who suffered SAE after ED disposition (3147ng/L, p=0.001), and among the 35 patients with cardiac SAE after ED disposition (2016.2ng/L, p=0.02). While there was a trend to higher levels among patients who suffered arrhythmia after the ED visit, it was not statistically significant (1776.4ng/L, p=0.07). In a model with CSRS predictors, the adjusted odds ratio for NT pro-BNP was 8.0 (95%CI 1.8, 35.9) and troponin was 3.8 (95%CI 1.7, 8.8). The addition of NT pro-BNP did not significantly improve the classification performance (p=0.76) with areas under the curves for CSRS was 0.91 (95%CI 0.88, 0.95) and CSRS with NT pro-BNP was 0.92 (95%CI 0.88, 0.95). Conclusion: In this multicenter study, mean NT pro-BNP levels were significantly higher among ED syncope patients who suffered SAE including cardiac SAE after ED disposition. Though NT pro-BNP was a significant independent predictor of SAE after ED disposition, it did not improve accuracy in ED syncope risk-stratification when compared to CSRS. Hence, we do not recommend NT pro-BNP measurement for ED syncope management.