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Abstract Objectives This study sought to estimate the likelihood of a motor vehicle accident causing serious risk or harm in patients with frequent vasovagal syncope, and compare this with international accident data. Background Recurrent vasovagal syncope poses a risk because of fainting while driving, but prospective, benchmarked estimates of this risk have not been reported. Methods Data were from the POST (Prevention of Syncope Trial)-1 and -2, which were multicenter randomized studies of patients with ≥3 lifetime vasovagal syncope spells. POST-1 patients (reported in 2005) received metoprolol or placebo for ≤1 year between 1998 and 2004; POST 2 patients received fludrocortisone or placebo for ≤1 year between 2006 and 2011. Accident data were recovered from Internet reports from the United States, United Kingdom, and Canada. Results A total of 418 patients (age 38 ± 17 years) had a median of 10 lifetime faints and a median of 3 faints in the previous year. Total follow-up time was 323 years, or 0.77 years per person. A total of 174 subjects fainted, having a total of 615 faints. Two patients fainted while driving, without fatality or injury, with a likelihood of 0.62% per person-year. The risk of serious harm or death was <0.0035% per person-year, and 0.0018% per faint. In the general U.S., U.K., and Canadian driving populations, the risk of serious harm or death was 0.067% per driver-year, and the risk of death was 0.009%. Conclusions The estimated risk of serious harm or death was <0.0035% per person-year in highly symptomatic patients, less than the risk of serious harm or death in the general population. (A Randomized Clinical Trial of Fludrocortisone for Vasovagal Syncope: The Second Prevention of Syncope Trial [POST II]; NCT00118482 )