Objectives. A double-blind randomised trial was designed to determine the efficacy of intravenous and oral disopyramide phosphate in preventing neurally syncope induced by a head-up tilt test.Background. Neurally mediated syncope is a frequent cause of syncope and may be induced by head-up tilt, testing. Recent uncontrolled trials have suggested that disopyramide may be an effective therapy in patients with neurally mediated syncope.Methods. Twenty-two consecutive patients with recurrent neurally mediated syncope and two or successive positive head-up tilt test responses were randomly allocated to receive either intravenous disopyramide or placebo. Head-up tilt testing at 60 ° was performed for 15 min. If presyncope or syncope was not provoked, isoproterenol infusion was started at a rate of 1 μg/min and the rate gradually increased until a 25% increase in heart rate was achieved. Eleven patients were subsequently randomised in crossover fashion to receive oral disepyramide (800 mg/day) or placebo during 1 week. The primary end point was prevention of syncope or presyncope provoked by head-up tilt testing.Results. Head-up tilt test results were positive for syncope in 12 (75%) of 16 patients receiving intravenous placebo and in 12 (60%) of 20 patients receiving disopyramide (p = 0.55 Fisher exact test, 95% confidence interval [CI] −14% to 40%).In the intravenous phase, complete crossover was achieved in 15 patients. Head-up tilt test results during this were positive in 13 patients (87%) receiving placebo and in 12 patients (80%) receiving disopyramide (p = 0.50 Fisher exact test, 95% CI −19% to 32%) and were positive in all patients receiving their initially randomized drug or placebo. In the oral phase, head-up tilt results were positive in only two patients (18%) assigned to placebo and in three patients (27%) receiving disopyramide (p = 0.54 Fisher exact test, 95% CI −42% to 24%).A mean follow-up time of 29 ± 8 months was obtained in 21 of the 22 patients. Syncope recurred in 3 (27%) of the 11 patients receiving disopyramide and 3 (30%) of the 10 patients not treated pharmacologically (p > 0.05).Conclusions. Intravenous disopyramide was ineffective for the prevention of neurally mediated syncope provoked by head-up tilt testing. No significant effect was observed after oral therapy with disopyramide. There was a striking decrease in the incidence of positive tilt test results over time regardless of intervention, thus discouraging the use of head-up tilt as the single method of assessing therapeutic efficacy. Recurrence of syncope after the investigative protocol was infrequent over long-term follow-up regardless of treatment group.