BACKGROUND: Increased work of breathing or fatigue of respiratory muscles has been suggested to reduce exercise performance. PURPOSE: The present study investigated the effects of continuous inspiratory resistive breathing (IRB) on the responsiveness of corticospinal pathway innervating the vastus lateralis (VL) to determine whether respiratory muscle fatigue affects the central motor output to exercising limb muscles. METHODS: Eight subjects underwent a 6-min IRB trial three times (IRB1-3) in two experiments. During each IRB trial, the subjects performed voluntary hyperventilation through a mask attached with an inspiratory resistive load (approximately 30% of maximal inspiratory pressure (Plmax)). In Experiment 1, Plmax was measured at baseline and after each IRB trial. In Experiment 2, VL responses to transcranial magnetic stimulation (motor evoked potentials (MEPs) and cortical silent periods were assessed during 5 s isometric knee extension at an intensity of 15% of the maximal voluntary contraction over the same time course as in Experiment 1. RESULTS: Plmax decreased from baseline after IRB2 and IRB3 (P < 0.05). MEPs increased from baseline after IRB1 and IRB2 (P < 0.05), whereas MEPs after IRB3 were not significantly different from baseline. Cortical silent periods did not change from baseline after IRB1 and IRB2, whereas cortical silent periods after IRB3 increased from baseline (P < 0.05). CONCLUSION: These results suggest that as inspiratory muscle fatigue progresses, the corticospinal tract controlling the lower limb muscles can shift from excitatory dominance to inhibitory dominance as a whole, affecting the central motor output to working limb muscles.