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Introduction The understanding of fatigue in hypoxia is limited due to: lack of control in arterial saturation, different exercise intensities and hypoxia levels, lag time between exercise cessation and fatigue evaluation. We aimed at evaluating fatigue during cycling and immediately after exhaustion (EXH) in normoxia, moderate and severe hypoxia at relative and absolute intensities. Methods Thirteen subjects completed three sessions in normoxia, moderate, and severe hypoxia with intensity based on percentage of normoxic maximal power output (NOR, MODABS, SEVABS) plus two sessions where intensity was based on the corresponding environmental condition (MODREL, SEVREL). Arterial saturation was clamped at 85% and 70% in moderate and severe hypoxia, respectively. Before, during cycling, and at EXH, maximum voluntary contraction (MVC), peripheral fatigue (high-frequency doublet [Db100], twitch [Pt]), and central fatigue (cortical voluntary activation [VATMS]) were evaluated without delay using an innovative ergometer. Results Time to EXH declined not only with hypoxia level at absolute but also relative intensities compared to NOR. At isotime, MVC, Pt, and Db100 were similarly depreciated in NOR, MODREL, and SEVREL. At EXH, there was a similar reduction among conditions in MVC (-26% to -31%), Db100 (-25% to -35%) and VATMS (-9% to -13%). However, Pt was less decreased in SEVREL compared with NOR (-33% ± 17% vs -46% ± 16%). Conclusions The shorter time to EXH in relative hypoxia and yet lower peripheral fatigue and similar central fatigue compared with normoxia suggests that hypoxia per se may affect brain areas not directly implicated in quadriceps motor function.