Background: Neuroimaging studies of major depressive disorder (MDD) indicate interhemispheric differences in prefrontal cortical activity (right greater than left). Aims: To investigate whether there are any interhemispheric differences of motor cortical excitability in MDD. Method: Eight patients with treatment-refractory MDD off medication were assessed for the severity of their depression, and transcranial magnetic stimulation studies (bilateral motor threshold and paired-pulse studies) were conducted. Eight normal controls were also studied. Results: MDD patients showed significant interhemispheric differences in motor threshold and paired-pulse curves, both of which showed lower excitability on the left hemisphere. Such differences were absent in controls. Conclusions: Our findings may aid the further understanding of the neurophysiology underlying MDD. Declaration of interest This study was supported in part by the Cellular Science Research Foundation, Yoshida Science Foundation, Stanley Vada Foundation, National Alliance for Research in Schizophrenia and Depression, and the National Institute of Mental Health (ROIMH57980).