Over 50% of people who rapidly ascend to extreme altitudes develop various symptoms known as acute mountain sickness (AMS), which rarely can be life threatening. It is unclear why some people are more susceptible to AMS than others. Our objective was to determine whether patent foramen ovale (PFO) is a risk factor for AMS. Subjects who had hiked to altitudes above 10,000' (~3,000 meters) on the John Muir Trail in California were recruited. Participants completed a questionnaire and two-physician adjudication was performed in regard to AMS status. A transcranial Doppler with agitated saline contrast injection was performed to evaluate the presence or absence of PFO. The primary outcome was the development of AMS. From 2016 to 2018, 137 hikers were recruited into the study. There was a higher prevalence of PFO in hikers with AMS 15/24 (63%) compared to hikers without AMS 44/113 (39%); p = 0.034. In the multivariate model, the presence of a PFO significantly increased the risk for developing AMS: OR 4.15, 95% CI 1.14-15.05; p = 0.030. In conclusion, hikers with a PFO had significantly higher risk of developing AMS relative to hikers without a PFO. Clinicians should consider PFO a risk factor in people who plan to hike to high altitudes.