Recurrent episodes of neurocardiogenic syncope that occur without warning are a common cause of recurrent syncope that can be identified during head upright tilt table testing. While the use of beta blockers, theophyllines, fludrocortisone, disopyramide, and serotonin reuptake inhibitors can be useful in the prevention of episodes, some patients are either unresponsive to or poorly tolerant of these agents. We investigated the use of the peripheral alpha stimulating agent midodrine in preventing both tilt-induced and spontaneous neurocardiogenic syncope. Twenty-five patients (16 women, 9 men, mean age 30 +/- 23 years) with severe recurrent syncope and a positive head upright tilt table study (refractory to or intolerant of standard therapies) were placed on midodrine 5-10 mg orally three times per day, (two patients required 15 mg/day). Of these, twelve became asymptomatic and five had a marked reduction in symptoms. We conclude that midodrine may be an effective therapy in patients with recurrent neurocardiogenic syncope refractory to other forms of therapy.