This study was undertaken to assess the value of sublingual nitroglycerin administration during upright tilt as a simple practical test for the diagnosis of vasovagal syncope. To this purpose, 235 patients with syncope of unknown origin and no evidence of organic heart disease (110 men, mean age 52 +/- 20 years) and 35 asymptomatic control subjects underwent head-up tilt testing with nitroglycerin challenge. Patients and subjects were tilted at 60 degrees for 45 + 20 minutes; the initial 45 minutes were without medication and the final 20 minutes after 300 micrograms of sublingual nitroglycerin. During the drug-free phase of the test, 59 patients (25%) and no controls had a positive response. After drug administration, a positive response (syncope in association with sudden hypotension and bradycardia) occurred in 60 patients (26%) and in 2 controls (6%), whereas an exaggerated or false-positive response (minor or different symptoms in association with slowly increasing hypotension alone) was observed in 33 patients (14%) and in 5 controls (14%). We conclude that the sublingual nitroglycerin head-up tilt test is a useful tool to unmask the vasovagal origin of unexplained syncope in patients without organic heart disease. The addition of nitroglycerin to upright tilt allows the positive rate of passive tilting to be doubled (51% vs 25%) while maintaining a high specificity (94% vs 100%).