Previous work has shown that mental fatigue may have negative consequences on cognitive or physical performance, although recent reports question this previous empirical evidence. Here, we investigate the critical role of inter-individual differences in susceptibility to develop mental fatigue by measuring neurophysiological and physical responses to an individualized mental fatigue task. We expected mental load to alter both subjective, i.e., increased subjective perception of fatigue, and objective markers of fatigue, i.e., impaired knee extensor neuromuscular function, impaired corticospinal excitability and reduced cerebral oxygenation. Even though all participants performed a similar mental effort, their performance in a subsequent exercise did not differ. Furthermore, even if there was an elevated subjective feeling of mental fatigue, none of the neurophysiological parameters were affected. The study provides new insights into an issue that has grown in popularity in recent years without questioning individual differences and which has taken for granted the detrimental effect of acute mental fatigue on performance.

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