The pathophysiology of human narcolepsy is still poorly understood. The hypoactivity of some neurotransmitter systems has been hypothesised on the basis of the canine model. To determine whether narcolepsy is associated with changes in excitability of the cerebral cortex, we assessed the excitability of the motor cortex with transcranial magnetic stimulation (TMS) in 13 patients with narcolepsy and in 12 control subjects. We used several TMS paradigms that can provide information on the excitability of the motor cortex. Resting and active motor thresholds were higher in narcoleptic patients than in controls and intracortical inhibition was more pronounced in narcoleptic patients. No changes in the other evaluated measures were detected. These results are consistent with an impaired balance between excitatory and inhibitory intracortical circuits in narcolepsy that leads to cortical hypoexcitability. We hypothesise that the deficiency of the excitatory hypocretin/orexin-neurotransmitter-system in narcolepsy is reflected in changes of cortical excitability since circuits originating in the lateral hypothalamus and in the basal forebrain project widely to the neocortex, including motor cortex. This abnormal excitability of cortical networks could be the physiological correlate of excessive daytime sleepiness and it could be the substrate for allowing dissociated states of wakefulness and sleep to emerge suddenly while patients are awake, which constitute the symptoms of narcolepsy.