Maintenance of arterial blood gases is achieved through sophisticated regulation of ventilation, mediated by both central and peripheral chemoreceptors. Central chemoreceptors detect changes in CO2 within the brainstem, whereas peripheral chemoreceptors are sensitive to changes in PaCO2 and PaO2. Respiratory chemoreflexes are of particular importance during exposure to high-altitude due to the competing influence and presence of both hypoxia and hypoxic ventilatory response-mediated hypocapnia on steady-state ventilatory drive. Large inter-individual variability exists in ventilatory responsiveness and acclimatization between individuals during ascent to high altitude, potentially affecting the development of acute mountain sickness (AMS). The relationship between ventilatory acclimatization to high-altitude and the development of acute mountain sickness (AMS) remains unclear, and no predictive test of AMS severity is available. We aimed to quantify ventilatory acclimatization in the context of high-altitude hypoxia by comparing differential ascent and descent values (i.e., hysteresis) in cardiorespiratory variables. We hypothesized that (a) the hysteresis area formed by cardiorespiratory variables during ascent and descent would quantify the magnitude of ventilatory acclimatization, and (b) larger hysteresis areas in ventilatory acclimatization would be associated with lower AMS symptom scores. We quantified the cardiorespiratory ascent-descent hysteresis areas in the pressure of end-tidal (PET)CO2 (Torr), peripheral oxygen saturation (SpO2; %), ventilation (L/min), chemoreceptor stimulus index (SI; PETCO2/SpO2) and the calculated steady-state chemoreflex drive (SS-CD; VE/SI) using portable devices (capnograph, peripheral pulse oximeter and respirometer, respectively) and assessed AMS severity symptoms using the Lake Louise Questionnaire in 25 healthy, Diamox-free trekkers ascending to and descending from 5160m in the Nepal Himalaya over 18 days. We found that (a) ascent-descent hysteresis was present in all cardiorespiratory variables, (b) large SS-CD responders (i.e., larger hysteresis in SS-CD) had lower AMS scores during ascent than low SS-CD responders, (c) AMS positive (3+) participants had lower SS-CD hysteresis areas than AMS negative (0-2), and (d) worst AMS scores during ascent were significantly, moderately and inversely-correlated to SS-CD hysteresis magnitude. We propose that ascent-descent hysteresis is a novel and feasible way to quantify cardiorespiratory acclimatization during incremental ascent to high altitude and may have broad utility given the high number of people who trek to altitude annually.