The aim of our present study was to assess the value of nitroglycerin infusion during upright posture as a new provocative test for diagnosis of vasovagal syncope. To this purpose 40 patients with unexplained syncope (17 men and 23 women, mean age 47 years) and 25 asymptomatic control subjects with negative baseline head-up tilt underwent two other tilting tests, one during nitroglycerin infusion and one during isoproterenol infusion. The protocol of the nitroglycerin test consisted of a maximum of five successive stages of 5 minutes in the supine position plus 10 minutes 80-degree upright tilt at progressively increasing infusion rates (increments of 0.86 microgram/kg/hr every stage). During the nitroglycerin test a positive response (syncope in association with sudden hypotension and bradycardia) occurred in 21 (53%) patients with unexplained syncope, an exaggerated response (minor symptoms in association with slowly increasing hypotension alone) occurred in 10 (25%), a negative response in 9 (22%), and drug intolerance in 0. During the isoproterenol test these percentages were 25%, 25%, 32%, and 18%, respectively. Only 2 (8%) control subjects had a positive response to nitroglycerin test and 2 (8%) to isoproterenol test. Thus the nitroglycerin test seems to be a useful alternative tool for diagnosis of vasovagal syncope; it is equally specific but more sensitive and feasible than the isoproterenol test.