Understanding the process of successful adaptation to high altitude provides valuable insight into the pathogenesis of conditions associated with impaired oxygen uptake and utilization. Prepubertal children residing at low altitude show a reduced cerebrovascular response to exercise in comparison to adults, and a transient uncoupling of cerebral blood flow to changes in the partial pressure of end-tidal CO 2 (P ET CO 2 ); however, little is known about the cerebrovascular response to exercise in high-altitude native children. We sought to compare the cerebral hemodynamic response to acute exercise between prepubertal children residing at high and low altitude. Prepubertal children (n = 32; 17 female) of Sherpa descent (Sherpa children [SC]) at high altitude (3800 m, Nepal) and maturational-matched (n = 32; 20 female) children (lowland children [LLC]) residing at low altitude (342 m, Canada). Ventilation, peripheral oxygen saturation (S p O 2 ), P ET CO 2, and blood velocity in the middle and posterior cerebral arteries (MCA v and PCA v ) were continuously measured during a graded cycling exercise test to exhaustion. At baseline (BL), P ET CO 2 (-19 ± 4 mmHg, p < 0.001), S p O 2 (-6.0% ± 2.1%, p < 0.001), MCA v (-12% ± 5%, p = 0.02), and PCA v (-12% ± 6%, p = 0.04) were lower in SC when compared with LLC. Despite this, the relative change in MCA v and PCA v during exercise was similar between the two groups (p = 0.99). Linear regression analysis demonstrated a positive relationship between changes in P ET CO 2 with MCA v in SC (R 2 = 0.13, p > 0.001), but not in LLC (R 2 = 0.03, p = 0.10). Our findings demonstrate a similar increase in intra-cranial perfusion during exercise in prepubertal SC, despite differential BL values and changes in P ET CO 2 and S p O 2 .