The purposes of this study were to determine if the fatigability of the quadriceps femoris varies by biological sex under conditions of normal muscle blood flow and ischemia, and if differences in neuromuscular activation patterns exist. Young men and women (n=11/group; age 20–39 years) performed a sustained knee extension contraction at 25% of maximal force under conditions of occluded (OCC) and normal muscle blood flow (NON-OCC). Electromyographic (EMG) activity was recorded from the vastus lateralis (VL), rectus femoris (RF), vastus medialis (VM) and biceps femoris (BF) muscles, and analyzed for fatigue-induced changes in the amplitude and burst rate and duration (transient changes in motor unit recruitment) of the signal. Additionally, force fluctuations during the sustained contraction were quantified. Women had a longer time to task failure during the NON-OCC task [214.9±20.5 vs. 169.1±20.5 (SE) s] (P=0.02), but not during the OCC task (179.6+19.6 vs. 165.2±19.6 s). EMG data demonstrated sex differences in the neuromuscular activation pattern of the RF muscle and the collectively averaged QF muscles. During the NON-OCC and OCC tasks women achieved a higher relative activation of the RF at task failure than men (NON-OCC: 40.68±4.57 vs. 24.49±4.19%; OCC: 36.80±5.45 vs. 24.41±2.12%) (P=0.02 and 0.05, respectively). Also, during both tasks, they demonstrated a greater relative activation at task failure than men when an average of the VL, VM and RF was considered. Additionally, women exhibited a greater coefficient of variation in force fluctuations during the last-third of the fatiguing NON-OCC task (6.21±0.567 vs. 4.56±0.56%) (P=0.001). No sex differences in EMG burst rate or duration were observed, although there was a trend towards greater EMG burst rate of the RF in association with muscle fatigue in the women (P=0.09). Interestingly, the only neuromuscular activation variable that displayed a significant relationship with the time to task failure was the average relative EMG of the QF at task failure, and this relationship was observed under both experimental blood flow conditions (NON-OCC: r=0.47, P=0.03; OCC: r=0.44, P=0.04). These results indicate that sex differences in muscle blood flow and/or muscle metabolism are in part responsible for the female advantage in fatigue-resistance. Additionally, these findings suggest that men synergistically recruit the RF compartment to a lesser extent than women in association with muscle fatigue, and that women achieve an overall greater relative activation of the QF at task failure than men. However, the implications of these sex differences in neuromuscular activation patterns during fatiguing muscular contractions on the ability to withstand muscle fatigue (prolonged time to task failure) does not appear to be causally related.