A sensory disturbance limited to the hand or fingers and the corner of the mouth both on the same side constitutes the cheiro-oral syndrome (COS). Six patients with typical COS are described; in 5 of them a well-circumscribed lesion was found at different brain sites. Although this syndrome was formerly attributed to a parietal or thalamic lesion, a lesion at brainstem level also can cause COS. The pathogenetic explanation of this peculiar sensory symptom complex is a matter of debate and a new hypothesis is formulated. We advocate that when COS is encountered, especially if a history of migraine is lacking, a thorough neurological workup is called for.