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Objectives: The purpose of this study was to investigate the acute vascular and oxygenation responses to repeated sprint exercise during arm cycling with either blood flow restriction (BFR) or systemic hypoxia alone or in combination. Design: The study design was a single-blinded repeated-measures assessment of four conditions with two levels of normobaric hypoxia (400 m and 3800 m) and two levels of BFR (0% and 45% of total occlusion). Methods: Sixteen active participants (eleven men and five women; mean ± SD; 26.4 ± 4.0 years old; 73.8 ± 9.8 kg; 1.79 ± 0.07 m) completed 5 sessions (1 familiarization, 4 conditions). During each test visit, participants performed a repeated sprint arm cycling test to exhaustion (10 s maximal sprints with 20 s recovery until exhaustion) to measure power output, metabolic equivalents, blood flow, as well as oxygenation (near-infrared spectroscopy) of the biceps brachii muscle tissue. Results: Repeated sprint performance was decreased with both BFR and systemic hypoxia conditions. Greater changes between minimum-maximum of sprints in total hemoglobin concentration ([tHb]) were demonstrated with BFR (400 m, 45% and 3800 m, 45%) than without (400 m, 0% and 3800 m, 0%) (p < 0.001 for both). Additionally, delta tissue saturation index (TSI) decreased more with both BFR conditions than without (p < 0.001 for both). The absolute maximum TSI was progressively reduced with both BFR and systemic hypoxia (p < 0.001). Conclusions: By combining high-intensity, repeated sprint exercise with BFR and/or systemic hypoxia, there is a robust stimulus detected by increased changes in blood perfusion placed on specific vascular mechanisms, which were more prominent in BFR conditions.