Current data suggest that up to 60 % of patients presenting to the emergency department with syncope leave the hospital without a defined etiology. Prior studies suggest a prevalence of psychiatric disease as high as 26 % in patients with syncope of unknown etiology. The objective of this study was to determine whether psychiatric disease is associated with an increased incidence of syncope of unknown etiology. Prospective, observational, cohort study of consecutive ED patients >18 presenting with syncope was conducted from 6/03 to 7/06. Patients were queried in the ED and charts reviewed for a history of psychiatric disease and use of psychiatric medication. Data were analyzed using SAS v9.2 with Fisher's exact tests. We enrolled 518 patients who presented to the ED after syncope, 161 (31 %) did not have an identifiable etiology for their syncopal event; 166 patients (32 %) had a history of or current psychiatric disease. Among men with psychiatric disease, 37 % had an unknown etiology of their syncopal event, compared to 23 % of men without psychiatric disease (p = 0.04). However, among women with syncope of unknown etiology, there was no significant difference between those with and without psychiatric disease (34.4 vs. 32.7 %) with p = 0.77. Our results suggest that men with psychiatric disease have an increased incidence of syncope of unknown etiology. Given this relationship, clinicians might consider screening for psychiatric disorders in syncopal patients when no clear etiology can be identified.