This study evaluated the feasibility and efficacy of voluntary sustained hyperventilation during rapid ascent to high altitude for the prevention of acute mountain sickness (AMS). Study subjects (n=32) were volunteer participants in a 2-day expedition to Mount Leoneras (4954 m), starting at 2800m (base camp at 4120 m). Subjects were randomized to either: 1) an intervention group using the voluntary hyperventilation (VH) technique targeting an end-tidal CO2 (ETCO2)<20 mmHg; or 2) a group using acetazolamide (AZ). During the expedition, respiratory rate (28±20 vs. 18±5 breaths/min, mean±SD, P<0.01) and SpO2 (95%±4% vs. 89%±5%, mean±SD, P<0.01) were higher, and ETCO2 (17±4 vs. 26±4 mmHg, mean±SD, P<0.01) was lower in the VH group compared to the AZ group – as repeatedly measured at equal fixed intervals during the ascent – showing the feasibility of the VH technique. Regarding efficacy, the incidence of 6 (40%) subjects registering an LLS score≥3 in the VH group was non-inferior to the 3 (18%) subjects in the acetazolamide group (P=0.16, power 28%). Voluntary increase in minute ventilation is a feasible technique, but – despite the underpowered non-inferiority in this small-scale proof-of-concept trial – it is not likely to be as effective as acetazolamide to prevent AMS.