Increased cerebral blood flow resulting from altered capillary level autoregulation at high altitudes leads to capillary overperfusion and then vasogenic cerebral edema, which is the leading hypothesis of acute mountain sickness (AMS). However, studies on cerebral blood flow in AMS have been mostly restricted to gross cerebrovascular endpoints as opposed to the microvasculature. This study aimed to investigate ocular microcirculation alterations, the only visualized capillaries in the central neural system (CNS), during early-stage AMS using a hypobaric chamber. This study found that after high altitude simulation, the optic nerve showed retinal nerve fiber layer thickening (P=0.004-0.018) in some locations, and the area of the optic nerve subarachnoid space (P=0.004) enlarged. Optical coherence tomography angiography (OCTA) showed increased retinal radial peripapillary capillary (RPC) flow density (P=0.003-0.046), particularly on the nasal side of the nerve. The AMS-positive group had the largest increases in RPC flow density in the nasal sector (AMS-positive, Δ3.21±2.37; AMS-negative, Δ0.01±2.16, P=0.004). Among multiple ocular changes, OCTA increase in RPC flow density was associated with simulated early-stage AMS symptoms (beta=0.222, 95%CI, 0.009-0.435, P=0.042). The area under the receiver operating characteristics curve (AUC) for the changes in RPC flow density to predict early-stage AMS outcomes was 0.882 (95%CI, 0.746-0.998). The results further confirmed that overperfusion of microvascular beds is the key pathophysiologic change in early-stage AMS. RPC OCTA endpoints may serve as a rapid, noninvasive potential biomarker for CNS microvascular changes and AMS development during risk assessment of individuals at high altitudes.© 2023. Science China Press.