Various data support the pathogenetic significance of serum IgM autoantibodies against glycolipid GM1 in patients with multifocal motor neuropathy. Although some patients with this neuropathy have an extraneural lymphoma, IgM anti-GM1 glycolipid autoantibodies have not been investigated in these cases. We found IgM anti-GM1 autoantibody in the serum of a 52-year-old man who developed multifocal motor neuropathy that was associated with an extraneural diffuse large B-cell lymphoma. An autopsy showed severe widespread demyelination without lymphoma cell infiltration in the peripheral nerves. Immunofluorescent flow cytometry and thin-layer chromatographic immunostaining demonstrated that most of the anti-GM1 antibody in the serum was monoclonal IgM of lambda type, which was also demonstrable in secretory form on lymphoma cells. The antibody showed affinity for the Galbeta1-3GalNAc terminal disaccharide of glycolipids GM1 and GD1b, which both are widespread in peripheral nerve myelin. Enzyme-linked immunosorbent assay demonstrated that this antibody was much more abundant in lymphoma cell culture supernatant than in normal lymphocyte culture supernatant. Thus, our patient's B-cell lymphoma cells produced a monoclonal IgM lambda autoantibody against this terminal disaccharide residue. This antibody bound to glycolipids GM1 and GD1b in peripheral motor nerve myelin, presumably initiating formation of destructive immune complexes that caused multifocal motor neuropathy.