Epidural motor cortex stimulation (EMCS) is a therapeutic option for chronic, drug-resistant neuropathic pain, but its mechanisms of action remain poorly understood. In two patients with refractory hand pain successfully treated by EMCS, the presence of implanted epidural cervical electrodes for spinal cord stimulation permitted to study the descending volleys generated by EMCS in order to better appraise the neural circuits involved in EMCS effects. Direct and indirect (D- and I-waves) were produced depending on electrode polarity and montage and stimulus intensity. At low intensity, anodal monopolar EMCS generated D-waves, suggesting direct activation of corticospinal fibers, whereas cathodal EMCS generated I2-waves, suggesting transsynaptic activation of corticospinal tract. The bipolar electrode configuration used in chronic EMCS to produce maximal pain relief, generated mostly I3-waves. This result suggests that EMCS induces analgesia by activating top-down controls originating from intracortical horizontal fibers or interneurons but not by stimulating directly the pyramidal tract. The descending volleys elicited by bipolar EMCS are close to those elicited by transcranial magnetic stimulation using a coil with postero-anterior orientation. Different pathways are activated by EMCS according to stimulus intensity and electrode montage and polarity. Special attention should be paid to these parameters when programming EMCS for pain treatment.