Background Recurrent vasovagal syncope is common, responds poorly to treatment, and causes physical trauma and poor quality of life. Midodrine prevents hypotension and syncope during tilt tests in patients with vasovagal syncope. Objective To determine whether midodrine can prevent vasovagal syncope in usual clinical conditions. Design Randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT01456481). Setting 25 university hospitals in Canada, the United States, Mexico, and the United Kingdom. Patients Patients with recurrent vasovagal syncope and no serious comorbid conditions. Intervention Patients were randomly assigned 1:1 to placebo or midodrine and followed for 12 months. Measurements The primary outcome measure was the proportion of patients with at least 1 syncope episode during follow-up. Results The study included 133 patients who had had a median of 6 syncope episodes in the prior year (median age, 32 years; 73% female). Compared with patients receiving placebo, fewer patients receiving midodrine had at least 1 syncope episode (28 of 66 [42%] vs. 41 of 67 [61%]). The relative risk was 0.69 (95% CI, 0.49 to 0.97; P = 0.035). The absolute risk reduction was 19 percentage points (CI, 2 to 36 percentage points), and the number needed to treat to prevent 1 patient from having syncope was 5.3 (CI, 2.8 to 47.6). The time to first syncope was longer with midodrine (hazard ratio, 0.59 [CI, 0.37 to 0.96]; P = 0.035; log-rank P = 0.031). Adverse effects were similar in both groups. Limitation Small study size, young and healthy patients, relatively short observation period, and high proportion of patients from 1 center. Conclusion Midodrine can reduce the recurrence of syncope in healthy, younger patients with a high syncope burden. Primary funding source The Canadian Institutes of Health Research.