INTRODUCTION: Cardiac syncope heralds significantly higher mortality compared with syncope due to non-cardiac causes or unknown etiology, commonly considered a benign event. A few epidemiologic studies have examined the outcome of non-cardiac/unexplained syncope comparing individuals with and without syncope, but with controversial results. We performed a systematic review and meta-analysis to clarify whether history of non-cardiac/unexplained syncope is associated with increased all-cause mortality in the general population. METHODS AND RESULTS: Our systematic review of the literature published between January 1st , 1966, and March 31st , 2018 sought prospective, observational, cohort studies reporting summary-level outcome data about all-cause mortality in subjects with history of non-cardiac/unexplained syncope compared with syncope-free participants. Adjusted hazard ratios were pooled through inverse variance random-effect meta-analysis to compute the summary effect size. Meta-regression models were performed to explore the effect of age, cardiovascular risk factors or other potential confounders on the measured effect size. We identified 4 studies including 287,382 individuals (51.6% men; age, 64±12 years): 38,843 with history of non-cardiac/unexplained syncope and 248,539 without history of syncope. The average follow-up was 4.4 years. History of non-cardiac/unexplained syncope was associated with higher all-cause mortality (pooled adjusted hazard ratio 1.13; 95%CI:1.05-1.23). Meta-regression analysis showed a stronger positive relationship proportional to aging and increasing prevalence of diabetes and hypertension. CONCLUSION: This study-level meta-analysis showed that among older, diabetic and/or hypertensive individuals, history of non-cardiac/unexplained syncope, even in the absence of an obvious cardiac etiology, is associated with higher all-cause mortality.