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Headache is a common consequence of ascent to high altitudes, and acute mountain sickness shares many features with migraine. Evidence also suggests that the prevalence of migraine is increased in people living at both high and moderate elevations. Here we identify an increased occurrence of migraine aura with increasing elevation. Our findings are supported by multiple lines of clinical evidence including a chart review characterizing the phenotype, a systematic prospective cohort comparison between moderate and low elevation, cross-sectional data from a multicenter headache clinic registry, and a nationwide electronic medical record-based dataset. In data from mice housed in altitude chambers, we show that susceptibility to spreading depolarization is increased with simulated elevation, providing a candidate mechanism for the altitude phenotype. The increased susceptibility to aura and SD with elevation may provide a unique opportunity to develop targeted strategies for mitigation relevant to the nearly 1 billion people worldwide living at higher elevations worldwide.