Introduction: Given the wide proliferation of ultra-long endurance races, it is important to understand the physiological response of the athletes to improve their safety. We evaluated the cognitive and neurosensory effects on ultra-endurance athletes during the Transpyrénéa (866 Km, 65,000 m positive slope), held on the French Pyrenees. Materials and Methods: 40 athletes were enrolled (age 43.8 ± 8.8 years; 36 males). Olfactory and cognitive tests were performed before the race (T0, n = 40), at 166 kms (T1, n = 28), at 418 kms (T2, n = 20), and after the race (T3, 866 kms, n = 13). The effect of dehydration and sleep deprivation on cognitive features were also studied. Results: Olfactory function decreased during the race (T0: 24.9 ± 4.3 vs. T3: 22.8 ± 3.5, z = -2.678, p = 0.007), language fluency increased (T0: 10.8 ± 2.9; T1: 11.4 ± 2.7; T2: 12.9 ± 2.8; T3: 12.9 ± 3.0; χ² = 11.132, p = 0.011 for combined samples), whereas the Trail Making Test did not show any changes between pre- and post-race (T0 vs. T3 p = 0.697 for TMT-A, p = 0.977 for TMT-B). The mean aggregate sleeping time was 9.3 ± 5.4 h at T1, 22.4 ± 10.0 h at T2, 29.5 ± 20.5 h at T3, with a correlation with olfactory function (r = 0.644, p = 0.018), while Total Body Water (TBW) was not correlated with olfactory or cognitive scores. Conclusion: Physical activity and sleep restriction in ultra-endurance could transiently affect olfactory function, while verbal fluency improved, demonstrating a dissimilar mechanism of activation/deactivation in different cortical areas. Body water loss was uncorrelated to cognition. Further studies should clarify whether cognitive and sensory deficits occur even in absence of sleep restriction.

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