Individual variations in peripheral oxygen saturation (SpO2) during repeated sprints in hypoxia and their impact on exercise performance remain unclear despite fixed external hypoxic stimuli (inspired oxygen fraction: FiO2). This study examined SpO2 individual variations during repeated sprints in hypoxia and their impact on exercise performance. Thirteen highly-trained sprint runners performed 10 × 10-s cycle sprints with 30-s passive recoveries in normobaric hypoxia (FiO2: 0.150). Mean power output (MPO), post-sprint SpO2, and heart rate for each sprint were assessed. Sprint decrement score (Sdec), evaluating fatigue development, was calculated using MPO variables. Participants were categorized into a high saturation group (HiSat, n = 7) or a low saturation group (LowSat, n = 6) based on their mean post-sprint SpO2 (measured 10-15 s after each sprint). Individual mean post-sprint SpO2 ranged from 91.6% to 82.2%. Mean post-sprint SpO2 was significantly higher (P < 0.001, d = 1.54) in HiSat (89.1% ± 1.5%) than LowSat (84.7% ± 1.6%). A significantly larger decrease in Sdec (P = 0.008, d = 1.68) occurred in LowSat (-22.3% ± 2.3%) compared to HiSat (-17.9% ± 2.5%). MPO (P = 0.342 d = 0.55) and heart rate (P = 0.225 d = 0.67) did not differ between groups. There was a significant correlation (r = 0.61; P = 0.028) between SpO2 and Sdec. In highly-trained sprint runners, individual responses to hypoxia varied widely and significantly affected repeated sprint ability, with greater decreases in SpO2 associated with larger performance alterations (i.e., larger decrease in Sdec).