This study aimed to validate the San Francisco Syncope Rule for predicting serious outcomes in emergency department patients with syncope. 371 syncope patients were prospectively evaluated. 13.7% had a serious outcome within 30 days. The San Francisco Syncope Rule criteria (history of congestive heart failure, hematocrit <30%, abnormal ECG, complaint of shortness of breath, systolic blood pressure <90 mm Hg) had high sensitivity and specificity for predicting serious outcomes. The study validated that the San Francisco Syncope Rule is a valuable tool for risk stratifying syncope patients to guide clinical decision-making.