Key PointsQuestionWhat is the effect size estimation for the decrease in Pao2in healthy unacclimatized adults when traveling to high-altitude (HA) regions, and what factors are associated with Pao2at HA?FindingsIn this systematic review and meta-analysis including 53 prospective studies and 777 adult participants ascending to HA between 1524 m and 8730 m, the mean decrease in Pao2was 1.60 kPa for each kilometer of altitude gain. Target altitude (≥1500 m), age, and time spent at target altitude were significantly associated with Pao2.MeaningThis study’s finding of a Pao2effect size estimate in healthy individuals may improve the understanding of physiological mechanisms, assist in clinical interpretation of acute altitude illness in healthy individuals, and serve as a reference for physicians counseling patients with cardiorespiratory disease who are traveling to HA regions.