Objective: To determine the prevalence, predictors, and prognosis of patients with multiple potential causes of syncope. Patients and Methods: This is a retrospective cohort study with prospective follow-up of consecutive patients with syncope of uncertain cause who were referred to the electrophysiology service for syncope evaluation from January 1, 1996, through December 31, 1998. The main outcome measures were prevalence of multiple potential causes of syncope, survival of patients with multiple potential causes of syncope compared with survival of patients with a single cause, and clinical predictors of multiple potential causes of syncope. Results: A total of 987 patients were studied (mean ± SD age, 58.0±21.4 years; male, 550 [55.7%]). Multiple potential causes were present in 182 patients (18.4%). Patients with multiple potential causes of syncope had a lower survival rate at 4 years, 73.1% (95% confidence interval, 64.6%-82.8%), vs those with a single cause, 89.3% (95% confidence interval, 86.4%-92.2%) (P<.001). Multivariate predictors of multiple potential causes were older age, atrial fibrillation, use of cardiac medications, and New York Heart Association classification II, III, and IV. Conclusion: Of the patients evaluated for syncope, 18.4% had multiple potential causes. The presence of multiple potential causes was an independent predictor of increased mortality among patients with syncope.