Aim We compared the control of breathing and heart rate by hypoxia between high‐ and low‐altitude populations of Peromyscus mice, to help elucidate the physiological specializations that help high‐altitude natives cope with O2 limitation. Methods Deer mice (Peromyscus maniculatus) native to high altitude and congeneric mice native to low altitude (Peromyscus leucopus) were bred in captivity at sea level. The F1 progeny of each population were raised to adulthood and then acclimated to normoxia or hypobaric hypoxia (12 kPa, simulating hypoxia at ~4300 m) for 5 months. Responses to acute hypoxia were then measured during stepwise reductions in inspired O2 fraction. Results Lowlanders exhibited ventilatory acclimatization to hypoxia (VAH), in which hypoxia acclimation enhanced the hypoxic ventilatory response, made breathing pattern more effective (higher tidal volumes and lower breathing frequencies at a given total ventilation), increased arterial O2 saturation and heart rate during acute hypoxia, augmented respiratory water loss and led to significant growth of the carotid body. In contrast, highlanders did not exhibit VAH – exhibiting a fixed increase in breathing that was similar to hypoxia‐acclimated lowlanders – and they maintained even higher arterial O2 saturations in hypoxia. However, the carotid bodies of highlanders were not enlarged by hypoxia acclimation and were similar in size to those of normoxic lowlanders. Highlanders also maintained consistently higher heart rates than lowlanders during acute hypoxia. Conclusions Our results suggest that highland deer mice have evolved high rates of alveolar ventilation and respiratory O2 uptake without the significant enlargement of the carotid bodies that is typical of VAH in lowlanders, possibly to adjust the hypoxic chemoreflex for life in high‐altitude hypoxia.