Lesion site, etiology, and clinical signs were analyzed in 50 cases of unilateral or bilateral corneomandibular reflex. The reflex was seen most commonly in acutely ill patients with a reduced level of consciousness and elevated intracranial pressure (ICP). Large cerebral hemispheric lesions with secondary brainstem pressure, intrinsic lesions of the upper brain-stem or diencephalon, diffuse or metabolic processes (often accompanied by raised ICP), and involvement of corticobulbar pathways in amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) were the most common settings where the reflex occurred. The sign is useful in distinguishing structural from metabolic processes in acutely comatose patients, localizing lesions to the upper brainstem area, determining the depth of coma and its evolution, providing evidence of uncal or transtentorial herniation in acute cerebral hemisphere lesions, and suggesting involvement above the spinal level in cases of ALS and MS.