Background : Peripheral muscle weakness can be caused by both peripheral muscle and neural alterations.Although peripheral alterations cannot totally explain peripheral muscle weakness in COPD, the existence of anactivation deficit remains controversial. The heterogeneity of muscle weakness (between 32 and 57% of COPDpatients) is generally not controlled in studies and could explain this discrepancy. This study aimed to specificallycompare voluntary and stimulated activation levels in COPD patients with and without muscle weakness.Methods:Twenty-two patients with quadriceps weakness (COPDMW), 18 patients with preserved quadricepsstrength (COPDNoMW) and 20 controls were recruited. Voluntary activation was measured through peripheral nerve(VAperipheral) and transcranial magnetic (VAcortical) stimulation. Corticospinal and spinal excitability (MEP/Mmax andHmax/Mmax) and corticospinal inhibition (silent period duration) were assessed during maximal voluntary quadricepscontractions. Results : COPDMWexhibited lower VAcorticaland lower MEP/Mmax compared with COPDNoMW(p< 0.05). Hmax/Mmaxwas not significantly different between groups (p= 0.25). Silent period duration was longer in the two groups of COPDpatients compared with controls (p< 0.01). Interestingly, there were no significant differences between all COPDpatients taken together and controls regarding VAcorticaland MEP/Mmax. Conclusions : COPD patients with muscle weakness have reduced voluntary activation without altered spinalexcitability. Corticospinal inhibition is higher in COPD regardless of muscle weakness. Therefore, reducedcortical excitability and a voluntary activation deficit from the motor cortex are the most likely corticalmechanisms implicated in COPD muscle weakness. The mechanisms responsible for cortical impairment andpossible therapeutic interventions need to be addressed.