Objectives: To evaluate the focal nature of the early and late inhibition of corticospinal neurons demonstrated by a paired-pulse stimulation paradigm.Methods: We performed paired-electric pulse stimulation studies using subdural electrodes implanted in 4 patients with intractable partial epilepsy.Results: Inhibition of motor evoked potentials in the first dorsal interosseous muscle was obtained by paired-pulse stimulation of the hand motor cortex (M1) with a subthreshold conditioning stimulus at conditioning-test intervals between 1 and 6ms. This early inhibition was abolished when the conditioning stimulus was moved to the sensory cortex (S1) or the arm M1. The inhibition was also produced by paired-pulse stimulation of the hand M1 with a suprathreshold conditioning stimulus between 50 and 300ms in all 3 patients. This late inhibition was still recognized when moving the conditioning stimulus to the hand S1 only in one of 3 patients.Conclusions: The early inhibition arises from very small areas in the M1 and is little mediated by neuronal circuits in the S1. On the other hand, the focal nature of the late inhibition is complicated and it arises mainly from the M1 but the S1 may be related to the generation of the late inhibition in some cases.