Fatigue and muscle pain perceived during high-intensity exercise has long been implicated in attenuation of exercise tolerance, but the influence of these perceptual responses on regulation of neuromuscular performance during exercise is unknown. PURPOSE: To examine the effects of pre-induced fatigue and concurrent rising pain (evoked by muscle ischemia) in one leg on motor fatigability and corticospinal excitability and inhibition of the contralateral leg. METHODS: Twelve healthy males(mean±SD; age: 27±4 yrs) undertook four experimental protocols including unilateral cycling to task failure at 80% of peak power output with i) the right-leg (RL), ii) the left-leg (LL), iii) RL immediately preceded by LL protocol (FAT-RL), and (iv) RL while blood flow was occluded in the contralateral (left) leg (PAIN-RL). The single-leg cycling exercise and neuromuscularassessments were carried out on a validated custom-built recumbent cycle ergometer that facilitates post-fatigue assessments within 1 second. Participants performed maximal and submaximal 5-s right-leg knee extensions, during which transcranial magnetic and femoral nerve electrical stimuli were delivered to elicit motor evoked potentials (MEP) and compound muscle action potentials (Mmax), respectively. RESULTS: Pre-induced fatigue reduced the right leg cycling time-to-task failure (332±137 s) to a greater extent than concurrent pain (460±158 s), compared to RL (580±226 s) (p<0.001).The maximal voluntary contraction (MVC) force declined less following FAT-RL (p<0.019) and PAIN-RL (p<0.032), compared to the RL. Voluntary activation declined, and the corticospinal excitability recorded from knee extensors increased similarly following the three conditions(p<0.05). However, the pre-induced fatigue, but not concurrent rising pain, reduced corticospinal inhibition compared to RL (p<0.05). CONCLUSIONS: These findings suggest that regardless of the origin or mechanisms modulating sensory group III/IV afferents (i.e. pre-induced fatigue vs. concurrent rising pain), the limit of exercise tolerance remains the same and exercise will be terminated upon achievement of sensory tolerance limit. The inhibitory neural feedback evoked by the two interventions however may have distinctive effects on corticospinal inhibition.