Hyperventilation and decreased metabolic rate are commonly observed in newborns during acute hypoxia; whether these responses are also present during sustained hypoxia is not known. We asked whether infants at high altitude had higher ventilation and lower metabolism than lowlanders. Ventilation (VE), oxygen consumption (VO2), and carbon dioxide production (VCO2) were measured in newborn (< 1 day old) full-term infants in La Paz (altitude 3,800 m; inspired oxygen pressure [PIO2], 92 mm Hg) and in Santa Cruz (altitude, 400 m; PIO2, 141 mm Hg), Bolivia. Each group consisted of 30 infants selected to have similar body weight. The mothers, Amerindians and mestizos, were born in the corresponding cities or at equivalent altitudes. Despite the lower inspired oxygen concentration in La Paz (0.107 ml STPD O2/ml BTPS air) than in Santa Cruz (0.164), neither VE nor VO2 or VCO2 differed between the two groups. The breathing pattern was deeper and slower at high altitude. From the values of VE and VO2 it was calculated that high-altitude infants extracted more O2 (+62%) from the inspired air than did the lowlanders. When given pure O2 to breathe, both groups of infants similarly increased VE and gaseous metabolism; even during hyperoxia, however, the ventilatory O2 extraction was higher (+50%) in the highlanders. We conclude that, contrary to what is observed in acute hypoxia, infants at high altitude maintain metabolic rate with no major alterations in VE. The ability to use a greater fraction of the inspired O2 at high altitude probably results from functional and structural alterations stimulated by fetal hypoxia.