Studies have reported that natriuretic peptides provide prognostic information for emergency department (ED) syncope. To evaluate whether adding N-terminal pro-B-type natriuretic peptide (NT-proBNP) to the Canadian Syncope Risk Score (CSRS) improves prediction of 30-day serious adverse events (SAEs). Prospective cohort study. 6 EDs in 2 Canadian provinces. 1452 adult ED patients with syncope. Serum NT-proBNP was measured locally at 1 site and batch processed at a central laboratory from other sites. The concentrations were not available to treating physicians or for adjudication of outcomes. An adjudicated composite outcome of 30-day SAEs, including death and cardiac (arrhythmic and nonarrhythmic) and noncardiac events. Of 1452 patients enrolled, 152 (10.5% [95% CI, 9.0% to 12.1%]) had 30-day SAEs, 57 (3.9%) of which were identified after the index ED disposition. Serum NT-proBNP concentrations were significantly higher among patients with SAEs than those without them (median, 626.5 ng/L vs. 81 ng/L; P < 0.001). Adding NT-proBNP values to the CSRS did not significantly improve prognostication (c-statistic, 0.89 and 0.90; P= 0.12 for difference), regardless of SAE subgroup or whether the SAE was identified after the index ED visit. The net reclassification index shows that NT-proBNP would have correctly reclassified 3% of patients with SAEs at the expense of incorrectly reclassifying 2% of patients without SAEs. Our study was powered to detect a 3% difference in the area under the curve. The heterogeneity of outcomes and robust baseline discrimination by the CSRS will make improvements challenging. Although serum NT-proBNP concentrations were generally much higher among ED patients with syncope who had a 30-day SAE, this blood test added little new information to the CSRS. Routine use of NT-proBNP for ED syncope prognostication is not recommended. Physicians' Services Incorporated Foundation, Canadian Institutes of Health Research, and The Ottawa Hospital Academic Medical Organization.