Westwood, Jessica, India Mayhook-Walker, Ciaran Simpkins, Andrew Darby-Smith, Dan Morris, and Eduardo Normando. Retinal vascular changes in response to hypoxia: a high-altitude expedition study. High Alt Med Biol. 25:49-59, 2024. Background: Increased tortuosity and engorgement of retinal vasculature are recognized physiological responses to hypoxia. This can lead to high-altitude retinopathy (HAR), but incidence reports are highly variable, and our understanding of the etiological mechanisms remains incomplete. This study quantitatively evaluated retinal vascular changes during an expedition to 4,167 m. Methods: Ten healthy participants summited Mount Toubkal, Morocco. Fundus images were taken predeparture, daily throughout the expedition, and 1 month postreturn. Diameter and tortuosity of four vessels were assessed, in addition to vessel density and features of HAR. Results: Significant (p ≤ 0.05) increases in tortuosity and diameter were observed in several vessels on high-altitude exposure days. There was a strong correlation between altitude and supratemporal retinal artery diameter on days 2, 3, and 6 of the expedition (r = 0.7707, 0.7951, 0.7401, respectively; p < 0.05). There was a significant increase in median vessel density from 6.7% at baseline to 10.0% on summit day. Notably there were no incidences of HAR. Conclusion: Physiological but not pathological changes were seen in this cohort, which gives insight into the state of the cerebral vasculature throughout this expedition. These results are likely attributable to relatively low altitude exposure, a conservative ascent profile, and the cohort's demographic. Future study must include daily retinal images at higher altitudes and take steps to mitigate environmental confounders. This study is relevant to altitude tourists, patients with diabetic retinopathy or retinal vein occlusion, and critically ill patients.