Recurrent vasovagally mediated episodes of hypotension and bradycardia are a common cause of recurrent syncope that can be identified by head-upright tilt table testing. Although the use of beta blockers, transdermal scopolamine, disopyramide, and fludrocortisone may be helpful in preventing further episodes, some patients are intolerant of or respond poorly to each of these agents. Following anecdotal observations, we investigated the utility of fluoxetine (a serotonin re-uptake antagonist) in preventing head-upright tilt induced hypotension/bradycardia in patients unresponsive to or intolerant of standard therapy. Sixteen patients (7 men and 9 women, mean age 42 +/- 21 years) with recurrent syncope and positive head-upright tilt studies (refractory to normal therapy) were placed on fluoxetine and restudied 5-6 weeks afterward. Three patients were intolerant of the medication. Of the 13 patients who underwent repeat tilt studies, seven patients (53% of the patients retested or 44% of the total group) were rendered tilt table negative, and, over a mean follow-up period of 19 +/- 9 months, have remained asymptomatic. We conclude that fluoxetine may be an effective therapy in patients with recurrent vasovagally mediated syncope refractory to other forms of therapy.