Syncope is a common presentation to the Emergency Department (ED); however, appropriate management and indications for hospitalization remain an ongoing challenge. The objective of this study was to determine if a predefined decision rule could accurately identify patients with syncope likely to have an adverse outcome or critical intervention. A prospective, observational, cohort study was conducted of consecutive ED patients aged 18 years or older presenting with syncope. A clinical decision rule was developed a priori to identify patients at risk if they met any of the following 8 criteria: 1) Signs and symptoms of acute coronary syndrome; 2) Signs of conduction disease; 3) Worrisome cardiac history; 4) Valvular heart disease by history or physical examination; 5) Family history of sudden death; 6) Persistent abnormal vital signs in the ED; 7) Volume depletion; 8) Primary central nervous system event. The primary outcome was either a critical intervention or an adverse outcome within 30 days. Among 362 patients enrolled with syncope, 293 (81%) patients completed their 30-day follow-up. Of these, 201 (69%) were admitted. There were 68 patients (23%) who had either a critical intervention or adverse outcome. The rule identified 66/68 patients who met the outcome for a sensitivity of 97% (95% confidence interval 93-100%) and specificity of 62% (56-69%). This pathway may be useful in identifying patients with syncope who are likely to have adverse outcome or critical interventions. Implementation and multicenter validation is needed before widespread application.