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The present study was designed to provide further insight into the mechanistic basis for the improved exercise tolerance following ischemic preconditioning (IPC) by investigating key-determinants of performance and perceived fatigability. Using a randomized, counterbalanced, single-blind, sham-controlled, crossover design, 16 males performed an isometric time-to-exhaustion test with the knee extensors at 20% maximal voluntary torque (MVT) after an IPC and a sham treatment (SHAM). Those who improved their time-to-exhaustion following IPC performed a time-matched IPC trial corresponding to the exercise duration of SHAM (IPC tm ). Neuromuscular function was assessed before and after exercise termination during each condition (IPC, IPC tm , and SHAM) to analyze the impact of IPC on performance fatigability and its central and peripheral determinants. Muscle oxygenation (SmO 2 ), muscle activity, and perceptual responses (effort and muscle pain) were recorded during exercise. Performance fatigability as well as its central and peripheral determinants were quantified as percentage pre-post changes in MVT (ΔMVT) as well as voluntary activation (ΔVA) and quadriceps twitch torque evoked by paired electrical stimuli at 100 and 10 Hz (ΔPS100 and ΔPS10⋅PS100 –1  ratio), respectively. Time-to-exhaustion, performance fatigability, its determinants, muscle activity, SmO 2 , and perceptual responses during exercise were not different between IPC and SHAM. However, six participants improved their performance by >10% following IPC (299 ± 71 s) compared to SHAM (253 ± 66 s,  d  = 3.23). The time-matched comparisons (IPC tm  vs. SHAM) indicated that performance fatigability, its determinants, and SmO 2  were not affected, while effort perception seemed to be lower (η p  2  = 0.495) in those who improved their time-to-exhaustion. The longer time-to-exhaustion following IPC seemed to be associated with a lower effort perception (η p  2  = 0.380) and larger impairments in neuromuscular function, i.e., larger ΔMVT, ΔVA, and ΔPS10⋅PS100 –1  ratio ( d  = 0.71, 1.0, 0.92, respectively). IPC did neither affect exercise tolerance, performance fatigability, as well as its central and peripheral determinants, nor muscle activity, SmO 2 , and perceptual responses during submaximal isometric exercise. However, IPC seemed to have an ergogenic effect in a few subjects, which might have resulted from a lower effort perception during exercise. These findings support the assumption that there are ‘responders’ and ‘non-responders’ to IPC.

Ischemic Preconditioning Did Not Affect Central and Peripheral Factors of Performance Fatigability After Submaximal Isometric Exercise