New Findings: What is the central question of this study? What is the impact of oxygen on the circulatory responses to an isocapnic cold pressor test (CPT) in lowlanders and Andean highlanders? What is the main finding and its importance? Overall, the circulatory responses to an isocapnic CPT were largely unaltered with acute normobaric hypoxia and chronic hypobaric hypoxia exposure in lowlanders. However, the relationship between mean arterial pressure and common carotid artery diameter was dampened in hypoxic conditions. Furthermore, there were no differences in the circulatory responses to the CPT between lowlanders and Andean highlanders with lifelong exposure to high altitude. Abstract: The impact of oxygen on the circulatory responses to a cold pressor test (CPT) in lowlanders and Andean highlanders remains unknown. Our hypotheses were as follows: (i) in lowlanders, acute normobaric and hypobaric hypoxia would attenuate the common carotid artery (CCA) diameter response to the CPT compared with normobaric normoxia; (ii) Andean highlanders would exhibit a greater CCA diameter response compared with lowlanders; and (iii) a positive relationship between CCA diameter and blood pressure in response to the CPT would be present in both lowlanders and highlanders. Healthy lowlanders (n = 13) and Andean highlanders (n = 8) were recruited and conducted an isocapnic CPT, which consisted of a 3 min foot immersion into water at 0–1°C. Blood pressure (finger photoplethysmography) and CCA diameter and blood flow (Duplex ultrasound) were recorded continuously. The CPT was conducted in lowlanders at sea level in isocapnic normoxic and hypoxic conditions and after 10 days of acclimatization to 4300 m (Cerro de Pasco, Peru) in hypoxic and hyperoxic conditions. Andean highlanders were tested at rest at high altitude. The main findings were as follows: (i) in lowlanders, normobaric but not hypobaric hypoxia elevated CCA reactivity to the CPT; (ii) no differences in response to the CPT were observed between lowlanders and highlanders; and (iii) although hypobaric hypoxaemia reduced the relationship between CCA diameter and blood pressure compared with normobaric normoxia (P = 0.132), hypobaric hyperoxia improved this relationship (P = 0.012), and no relationship was observed in Andean highlanders (P = 0.261). These data demonstrate that the circulatory responses to a CPT were modified by oxygen in lowlanders, but were unaltered with lifelong hypoxic exposure.