We sought to determine the effects of prolonged moderate hypobaric hypoxia (HH) on cardiac baroreflex sensitivity (cBRS) in young women and whether these effects are a consequence of the reduced arterial oxygen (O) tension and/or increased pulmonary ventilation in HH. We hypothesized that HH would reduce cBRS and that this effect would be counteracted by acute restoration of the inspiratory partial pressure of O ([Formula: see text]) and/or voluntary attenuation of pulmonary ventilation. Twelve healthy women (24.0 ± 4.2 yr) were studied before () and twice during a sojourn in a hypobaric chamber (∼8 h, ; 4 days, ) where barometric pressure corresponded to ∼3,500-m altitude. Minute ventilation (V̇e; pneumotachometer), heart rate (electrocardiogram), and arterial pressure (finger volume clamp method) were recorded. cBRS was calculated using transfer function analysis between systolic pressure and RR interval. Assessments were made during ) spontaneous breathing and (in HH only), ) controlled breathing (reducing V̇e by ∼1 to 2 L/min), and ) breathing a hyperoxic gas mixture that normalized [Formula: see text]. During spontaneous breathing, HH decreased cBRS (12.5 ± 7.1, 8.9 ± 4.4, and 7.4 ± 3.0 ms/mmHg on , , and , respectively; = 0.018). The normalization of [Formula: see text] increased cBRS (10.6 ± 3.3 and 10.7 ± 6.1 ms/mmHg on and ) in HH compared with values observed during spontaneous breathing ( < 0.001), whereas controlled breathing had no effect on cBRS ( = 0.708). These findings indicate that ongoing arterial chemoreflex activation by the reduced arterial O tension, independently of the hypoxic ventilatory response, reduces cBRS in young women exposed to extended HH. We examined the effects of prolonged hypobaric hypoxia (corresponding to ∼3,500-m altitude) on cardiac baroreflex sensitivity (cBRS) in young women and investigated underlying mechanisms. We found that cBRS was reduced in hypoxia and that this reduction was attenuated by acute restoration of inspiratory oxygen partial pressure but not by volitional restraint of pulmonary ventilation. These findings help to elucidate the role of arterial chemoreflex mechanisms in the control of cBRS during hypobaric hypoxia in young women.