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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 hypoxic-normoxic 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.