Background: Nitroglycerin (NTG) challenge during head-up tilt-table testing (HUTT) is often utilized to determine the etiology of unexplained vascular syncope. However, conflicting results concerning nitrate-induced hemodynamic changes during HUTT have been reported. The purpose of this study was to assess the determinants of presyncopal symptoms during NTG-stimulated HUTT. Methods: We evaluated 40 patients with suspected vasovagal syncope. Beat-to-beat changes in blood pressure, heart rate (HR), cardiac index (CI), and systemic vascular resistance (SVR) during HUTT were measured with thoracic impedance cardiography and a plethysmographic finger arterial pressure monitoring device. Results: None of the 40 patients complained of presyncopal symptoms during passive HUTT. However, after the administration of NTG 28 patients showed presyncopal symptoms (NTG+ group) and the remaining 12 patients did not (NTG- group). HR, CI, and the stroke index did not significantly differ between the two groups, whereas mean arterial pressure and SVR were significantly lower in the NTG+ group. Conclusions: Presyncopal symptoms during NTG-stimulated HUTT are SVR mediated, not cardiac output mediated. This study challenges the conventional idea of a decrease in cardiac output mediated by NTG as the overriding cause of presyncopal symptoms during HUTT.