Key points: Females demonstrate greater fatigue resistance than males during contractions at intensities relative to maximum force. However, previous studies have not accounted for the influence of metabolic thresholds on fatigability. This study is the first to test whether sex differences in fatigability exist when exercise intensity is normalised relative to a metabolic threshold: the critical intensity derived from assessment of the intensity–duration relationship during intermittent, isometric knee extensor contractions. We show that critical intensity in females occurred at a higher percentage of maximum force compared to males. Furthermore, females demonstrated greater fatigue resistance at exercise intensities above and below this metabolic threshold. Our data suggest that the sex difference was mediated by lesser deoxygenation of the knee extensors during exercise. These data highlight the importance of accounting for metabolic thresholds when comparing fatigability between sexes, whilst emphasising the notion that male data are not generalisable to female populations. Abstract: Females are less fatigable than males during isometric exercise at intensities relative to maximal voluntary contraction (MVC); however, whether a sex difference in fatigability exists when exercise is prescribed relative to a critical intensity is unknown. This study established the intensity–duration relationship, and compared fatigability and recovery between sexes following intermittent isometric contractions normalised to critical intensity. Twenty participants (10 females) completed four intermittent isometric knee extension trials to task failure to determine critical intensity and the curvature constant (W′), followed by fatiguing tasks at +10% and −10% relative to critical intensity. Neuromuscular assessments were completed at baseline and for 45 min post-exercise. Non-invasive neurostimulation, near-infrared spectroscopy, and non-invasive haemodynamic monitoring were used to elucidate the physiological mechanisms responsible for sex differences. Females demonstrated a greater critical intensity relative to MVC than males (25 ± 3 vs. 21 ± 2% MVC, P = 0.003), with no sex difference for W′ (18,206 ± 6331 vs. 18,756 ± 5762 N s, P = 0.850). Time to task failure was greater for females (62.37 ± 17.25 vs. 30.43 ± 12.75 min, P < 0.001) during the +10% trial, and contractile function recovered faster post-exercise (P = 0.034). During the −10% trial females experienced less contractile dysfunction (P = 0.011). Throughout the +10% trial, females demonstrated lesser decreases in deoxyhaemoglobin (P = 0.007) and an attenuated exercise pressor reflex. These data show that a sex difference in fatigability exists even when exercise is matched for critical intensity. We propose that greater oxygen availability during exercise permits females to sustain a higher relative intensity than males, and is an explanatory factor for the sex difference in fatigability during intermittent, isometric contractions.