Background: A reduction in the inspired oxygen fraction (FiO2) induces a decline in arterial oxygen saturation (SpO2) and changes of heart rate variability (HRV). It has been shown that SpO2 and HRV responses to similar levels of acute normobaric hypoxia are inter-individual variable. Variable response may be influenced by normoxia reached maximal oxygen uptake (VO2max) value. Objective: The primary aim was to assess HRV and the SpO2 response to hypoxia, and examine the association with normoxic VO2max. Methods: Supine HRV and SpO2 were monitored during normobaric hypoxia (FiO2 = 9.6%) for 10 minutes in 28 subjects, aged 23.7 ± 1.7 years. HRV was evaluated by using both spectral and time domain HRV analysis. Low frequency (LF, 0.05-0.15 Hz) and high frequency (HF, 0.15-0.50 Hz) power together with square root of the mean of the squares of the successive differences (rMSSD) were calculated and transformed by natural logarithm (Ln). Based on the SpO2 in hypoxia, subjects were divided into Resistant (RG, SpO2 ≥ 70.9%, n = 14) and Sensitive (SG, SpO2 < 70.9%, n = 14) groups. Perceived hypoxia tolerance was self-scored on a 4-level scale. Results: VO2max was higher in SG (62.4 ± 7.2 ml · kg-1 · min-1) compared with RG (55.5 ± 7.1 ml · kg-1 · min-1, p =.017, d = 0.97). A significant relationship (r = -.45, p =.017) between hypoxicnormoxic difference in SpO2 and normoxic VO2max level was found. Vagal activity (Ln rMSSD) was significantly decreased (SG: p <.001, d = 2.64; RG: p <.001, d = 1.22), while sympathetic activity (Ln LF/HF) was relatively increased (p <.001, d = -1.40) in only the SG during hypoxia. Conclusions: Results show that subjects with a higher aerobic capacity exhibited a greater decline in SpO2, accompanied by greater autonomic cardiac disturbances during hypoxia. The SpO2 reduction was associated with perceived hypoxia comfort/discomfort. The hypoxia discomfort state was accompanied by a greater withdrawal in cardiac vagal activity.