Serum of patients with neuropathy and IgM monoclonal antibodies (M-proteins) that bind to the myelin-associated glycoprotein (MAG) were tested for binding to the major cross-reactive sulfated glucuronic acid containing glycosphingolipid, sulfated glucuronic acid paragloboside (SGPG). IgM binding to the glycolipid was detectable at serum dilutions of 1:10,000 and reactivity was greatest at 4 degrees C. Low titers of IgM binding to the glycolipid were also detected in sera from normal subjects and from patients with neurologic or rheumatologic diseases without serum M-proteins. Binding activity was present in 25% of the sera tested, and titers ranged between 1:25 and 1:400. One patient with peripheral neuropathy, however, had a measurable titer of 1:12,800 in the absence of monoclonal gammopathy. The study indicates that cold reacting anti-SGPG IgM antibodies are frequent constituents of the normal human antibody repertoire, and that monoclonal or polyclonal expansion of B cells that secrete these antibodies, is associated with peripheral neuropathy.