Cortico-hypoglossal projections were investigated in 11 patients with unifocal ischaemic lesions of different brainstem levels using transcranial magnetic stimulation. Lesion topography was documented by MRI studies. In seven patients the projections to the ipsi- and contralateral hypoglossal nuclei were separately affected. Pontine lesions at the ventral paramedian base close to the midline affect the contralateral projections while lateral lesions at the pontine base affect the ipsilateral projections. Lesions of the paramedian dorsal pontine base do not involve the cortico-hypoglossal projections. Our findings indicate that the cortico-hypoglossal fibres branch off the main ventral pyramidal tract. Lesions of the dorso- and mediolateral medulla impair only the ipsilateral projections. We conclude that ipsilateral projections enter the hypoglossal nucleus from its lateral aspect and that the contralateral projections cross the midline at the pontomedullary junction.