Background: A high prevalence of minor psychiatric disorders (MPDs) has been reported in patients with vasovagal syncope (VVS). However, the relationship between the psychiatric substrate and syncope remains unclear. Methods: In order to test the hypothesis that MPDs may predispose to VVS, we assessed the prevalence of syncope, the response to head-up tilt test (HUTT) and the efficacy of psychiatric drug treatment in reducing syncopal episodes, in patients with recently diagnosed MPDs. The response to HUTT was compared with that in an equal number of matched (a) patients with VVS and (b) healthy controls. Results: A high rate of patients with MPDs (58%) had a positive HUTT. Additionally, 45% had a history of syncope; among them, the rate of positive HUTT was identical to that in the VVS group (83%). Following psychiatric drug treatment, the number of patients with syncope decreased in the MPD group (6/67 from 30/67, p < 0.01). Psychiatric symptoms and quality of life were also improved. The number of syncopal spells decreased equally in the MPD and VVS groups (0.6 ± 0.5 from 2.5 ± 1.4, p < 0.01, and 0.7 ± 0.5 from 2.7 ± 1.3, p < 0.01, respectively). Conclusion: A high proportion of patients with MPDs experience syncope, associated with a high rate of positive HUTT, comparable to that observed in VVS. Psychiatric treatment results in the improvement of syncopal and psychiatric symptoms. These findings suggest involvement of co-occurring MPDs in the pathogenesis of VVS. Therefore, the diagnosis and treatment of MPDs, when present, may be crucial for the effective therapy of vasovagal syndrome.