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Purposes: This study quantified performance, physiological, and perceptual responses during resistance exercise to task failure with blood flow restriction (BFR), in systemic hypoxia, and with these stimuli combined.Methods: Fourteen young men were tested for 1-repetition maximum (1RM) in the barbell biceps curl and lying triceps extension exercises. On separate visits, subjects performed exercise trials (4 sets to failure at 70% 1RM with 90 s between sets) in six separate randomized conditions, i.e., in normoxia or hypoxia (fraction of inspired oxygen = 20.9% and 12.9%, respectively) combined with three different levels of BFR (0%, 45%, or 60% of resting arterial occlusion pressure). Muscle activation and oxygenation were monitored via surface electromyography and near-infrared spectroscopy, respectively. Arterial oxygen saturation, heart rate, and perceptual responses were assessed following each set.Results: Compared to set 1, the number of repetitions before failure decreased in sets 2, 3, and 4 for both exercises (all P < 0.001), independently of the condition (P > 0.065). Arterial oxygen saturation was lower with systemic hypoxia (P < 0.001), but not BFR, while heart rate did not differ between conditions (P > 0.341). Muscle oxygenation and activation during exercise trials remained unaffected by the different conditions (all P ≥ 0.206). A significant main effect of time, but not condition, was observed for overall perceived discomfort, difficulty breathing, and limb discomfort (all P < 0.001).Conclusion: Local and systemic hypoxic stimuli, or a combination of both, did not modify the fatigue-induced change in performance, trends of muscle activation or oxygenation, nor exercise-related sensations during a multi-set resistance exercise to task failure. [ABSTRACT FROM AUTHOR]