Peripheral neuropathy was found in 12 (46%) of 26 patients with macroglobulinemia. The neuropathy was subclinical in two. Anti-myelin-associated glycoprotein (MAG) activity was found in six (50%) patients with neuropathy. Sural nerve biopsies showed demyelination and IgM deposits on the myelin sheath. In one patient who had no anti-MAG activity, the serum IgM bound to peripheral myelin by indirect immunofluorescence and to several protein bands in peripheral nerve and other tissues by immunoblot. In the other five patients with neuropathy, we found no binding of M proteins to nerve components, but in three patients there were endoneurial IgM deposits in nerve biopsy. Peripheral neuropathy may be related to the antigen-specificity of M proteins.