What is the central question of this study? Does applying blood flow restriction during the rest periods of repeated sprint exercise in a hypoxic environment lead to greater local hypoxia within exercising muscles without compromising training workload? What is the main finding and its importance? Repeated sprint exercise with blood flow restriction administered during rest periods under systemic hypoxia led to severe local hypoxia within the exercised muscles without a reduction in power output. The maintained power output might be due to elevated neuromuscular activation. Accordingly, the proposed repeated sprint exercise in the current study may be an effective training modality. Repeated sprint exercise (RSE) is a popular training modality for a wide variety of athletic activities. The purpose of this study was to assess the combined effects of systemic hypoxia and blood flow restriction (BFR) on muscle deoxygenation and RSE performance. Twelve healthy young men performed a standard RSE training modality (five sets of 10 s maximal sprint with a 60 s rest) under four different conditions: (1) normoxic control (NC), normoxia (N, 20.9%) + control BFR (C, 0 mmHg); (2) normoxic BFR (NB), normoxia (N, 20.9%) + BFR (B, 140 mmHg); (3) hypoxic control (HC), hypoxia (H, 13.7%) + control BFR (C, 0 mmHg); and (4) hypoxic BFR (HB): hypoxia (H, 13.7%) + BFR (B, 140 mmHg). BFR was only administered during the rest period of the respective RSE trials. In the local exercising muscles, muscle oxygen saturation ( ) and neuromuscular activity were measured using near-infrared spectroscopy and surface electromyography, respectively. SmO2 was lower in systemic hypoxia conditions relative to normoxia conditions (P < 0.05). A rther decrease in SmO2 was observed in HB relative to HC (Set 1: HC 70.0 ± 17.5 vs. HB 57.4 ± 11.3%, P = 0.001; Set 4: HC 67.5 ± 14.6 vs. HB 57.0 ± 12.0%, P = 0.013; Set 5: HC 61.0 ± 15.3 vs. HB 47.7 ± 11.9%, P < 0.001). No differences in RSE performance were observed between any of the conditions (P > 0.05). Interestingly, an elevated neuromuscular activity was seen in response to the BFR, particularly during conditions of systemic hypoxia (P < 0.05). Thus, RSE with BFR administered during rest periods under systemic hypoxia led to severe local hypoxia without compromising training workload.