OBJECTIVE A double-blind randomized trial was designed to determine the efficacy of intravenous and oral disopyramide phosphate in preventing neurally mediated 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 more successive positive head-up tilt test responses were randomly allocated to receive either intravenous disopyramide or placebo. Head-up tilt testing at 60 degrees was performed for 15 min. If presyncope or syncope was not provoked, isoproterenol infusion was started at a rate of 1 microgram/min and the rate gradually increased until a 25% increase in heart rate was achieved. Eleven patients were subsequently randomized in crossover fashion to receive oral disopyramide (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 phase 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.