We report a 62-year-old woman with a past history of painful central visual loss who developed progressive quadriparesis and bulbar palsy. Neurological examination revealed widespread upper and lower motor neuron signs in the bulbar region and extremities. Electromyography demonstrated widespread active and chronic motor axon loss. Magnetic resonance neuroimaging studies revealed enhancing callosal and periventricular white matter lesions and cervical and thoracic cord hyperintensities. Cerebrospinal fluid analysis was consistent with multiple sclerosis. The patient died of respiratory failure two years after presentation, and autopsy revealed multifocal demyelination involving the corpus callosum, cerebellum and spinal cord as well as pathologic findings typical of amyotrophic lateral sclerosis. A review of the literature confirms the exceedingly unusual combination of amyotrophic lateral sclerosis with multiple sclerosis.