Central motor drive to active muscles is believed to be reduced during numerous exercise tasks to prevent excessive peripheral fatigue development. The purpose of the present study was to use hypoxia to exacerbate physiological perturbations during a novel, intermittent exercise task and to explore the time-course and interplay between central and peripheral neuromuscular adjustments. On separate days, 14 healthy men performed four sets of 6 × 5 maximal-intensity, isokinetic leg extensions (1 repetition lasting ∼7 s) at 300°/s (15 and 100 s of passive rest between repetitions and sets, respectively) under normoxia (NM, fraction of inspired O2 0.21), moderate (MH, 0.14), and severe normobaric hypoxia (SH, 0.10). Neuromuscular assessments of the knee extensors were conducted before and immediately after each set. There was an interaction between time and condition on the mean peak torque produced during each set (P < 0.05). RMS/M-wave activity of the rectus femoris decreased across the four sets of exercise, but there was no difference between conditions (8.3 ± 5.1% all conditions compounded, P > 0.05). Potentiated twitch torque decreased post set 1 in all conditions (all P < 0.05) with greater reductions following each set in SH compared with NM but not MH (end-exercise reductions 41.3 ± 3.0% vs. 28.0 ± 3.2%, P < 0.05 and 32.1 ± 3.3%, P > 0.05). In conclusion, severe hypoxia exacerbates both peripheral fatigue development and performance decrements during maximal, intermittent, dynamic leg extensions. In contrast to observations with other exercise modes, during exercise involving a single muscle group the attenuation of central motor drive does not appear to independently regulate the development of peripheral muscle fatigue.