Conventional tilt test protocols are time consuming and there is no consensus regarding the optimal duration of the test and the provocative drug to be used. This study evaluated the diagnostic power of a short nitroglycerine test against a conventional isoproterenol protocol. A cohort of 128 patients with unexplained syncope was studied. A group of 64 consecutive patients were tilted with a short nitroglycerine test consisting of a passive phase of 15 minutes and if this proved negative, 400 microg of sublingual nitroglycerin spray for a further 15 minutes. The control group consisted of 64 patients tilted with a conventional isoproterenol protocol with a passive phase of 30 minutes and a drug-challenge phase of 20 minutes. In the nitroglycerine protocol 39 (60.9%) patients showed a positive response versus 27(42.2%) in the isoproterenol group (P = 0.034). The duration of the protocol was 23.2 +/- 7.2 minutes in the nitroglycerine group versus 41.1 +/- 15.5 minutes with isoproterenol (P = 0.001). The time until syncope was 18.87 +/- 6.1 versus 29 +/- 18, respectively (P = 0.002). For evaluating unexplained syncope the short tilt test protocol with nitroglycerine is less time consuming, easier to perform, and has a higher rate of positive response than a conventional isoproterenol protocol.