New Findings: What is the central question of this study? Does ischaemic preconditioning (IPC) influence central and peripheral fatiguing mechanisms during sustained maximal isometric exercise? What is the main finding and its importance? Voluntary activation and pre- to postexercise reductions in resting twitch torque values were unchanged by IPC. However, an effect on tissue oxygenation was observed within the IPC trials, where greater concentrations of deoxyhaemoglobin were recorded with concurrent upward trends of total haemoglobin concentrations. Using a direct assessment of neural drive, we found that IPC had no influence on either central or peripheral fatiguing pathways after maximal isometric exercise. Abstract: Ischaemic preconditioning (IPC) is thought to inhibit neural feedback from metabolically sensitive muscle afferents during exercise. It was hypothesized that IPC could affect mechanisms associated with centrally mediated fatigue after a maximally fatiguing protocol. Eleven resistance-trained men completed three 2 min maximal voluntary contractions (MVCs) via an isometric leg extension preceded by treatments of IPC (three bouts of 5 min bilateral leg occlusions at 220 mmHg), SHAM (three bouts of 5 min at 20 mmHg) or CON (30 min passive rest). Femoral nerve stimulation was used to explore central and peripheral fatigue pathways. These pathways were profiled at baseline (BL), before the 2 min MVC (Pre) and 10 s afterwards (Post). Tissue oxygenation was measured throughout the 2 min MVCs via near-infrared spectroscopy. The Pre to Post MVC (−71 ± 56 Nm; d = 1.33 ± 0.51, P < 0.01) and twitch torque (−51 ± 20 Nm; d = 3.76 ± 0.84, P < 0.01) levels declined without differences between conditions (MVC, P = 0.67; twitch torque, P = 0.39). Voluntary activation was also unaffected by condition (P = 0.80). Peak deoxyhaemoglobin concentrations were elevated in the IPC trials relative to CON (3.7 ± 3.0 $μ$mol l−1; d = 1.02 ± 0.46, P < 0.01) and SHAM (3.0 ± 3.7 $μ$mol l−1; d = 0.82 ± 0.57, P < 0.05). These findings demonstrate that IPC does not affect central or peripherally mediated mechanisms of fatigue during a sustained 2 min maximal effort isometric leg-extension task.