In a study to determine the prevalence of monoclonal gammopathy (MG) among patients with motor neuron disease (MND), 6 out of 56 (10.7%) were found to have a monoclonal paraprotein. Of these 6 patients, 4 had an IgG and 2 had an IgA paraprotein. The clinical syndromes consisted of amyotrophic lateral sclerosis in 2 patients, lower motor neuron syndrome with preserved reflexes in at least one limb in 3 patients, and motor neuropathy with multifocal conduction block in 1 patient. The presence of gammopathy appears to correlate with the absence of marked upper motor neuron involvement and with elevated CSF protein concentration. An underlying malignant disorder was ruled out in all 6 patients, and they were considered to have MG of undetermined significance (MGUS). In a control group of 121 age-matched patients with other neuroimmunological disorders, 5 patients (4.13%) had MG. Four of these had gammopathy associated with malignant myeloma, and 1 had MGUS. These results support previous reports of increased prevalence of MGUS in patients with MND and suggest that an autoimmune mechanism may play a role in the disease.