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This study investigated the individual and combined effects of mental fatigue (MF) and hypoxia (HYP) on physical and cognitive performance. Fifteen males (24 ± 3 years) completed one familiarization session and six experimental trials, including: 1) normoxia (0.209 FiO2) and no MF; 2) normoxia (0.209 FiO2) with MF; 3) mild normobaric HYP (0.13 FiO2) and no MF; 4) mild normobaric HYP (0.13 FiO2) with MF; 5) severe normobaric HYP (0.10 FiO2) and no MF; 6) severe normobaric HYP (0.10 FiO2) with MF. Each condition included a 15-min self-paced time trial, followed by a 60-s isometric maximal voluntary contraction of the biceps brachii. MF was induced using a 16-min individualized cognitive test prior to exercise performance. Following each time trial, participants performed the Tower of Hanoi cognitive test. A main effect of HYP was observed on average power output, oxygen consumption and muscle oxygenation (P ≤ 0.004), with no effect of MF (P ≥ 0.599). Voluntary activation of the biceps brachii was also reduced in HYP (68.42 ± 5.64%, P = 0.039). No effect of MF or HYP was observed on cognitive performance (P ≥ 0.138). HYP impacted physical performance, whilst MF had no effect on self-paced physical or cognitive performance. [ABSTRACT FROM AUTHOR]