With increasing age, peripheral neuropathy becomes more common in multiple symmetric lipomatosis (MSL) and the principal cause of severe disability. High alcohol consumption is frequently associated and the peripheral neuropathy of MSL is often attributed to alcoholism. In this study, sural nerve biopsies from MSL patients revealed an absence of acute axonal degeneration, a significant shift to the left of myelinated fibre diameter distributions, reduced indices of axonal and nerve fibre circularity, and an increase in myelin periodicity. This pathology supports the view that the neuropathy of MSL is not alcohol-induced but that a chronic distal axonopathy is an integral part of the MSL syndrome. Biochemical observations suggest a defect in catecholamine-stimulated lipolysis in MSL at a membrane level, possibly in the amount or function of Gs membrane protein or in the catalytic unit of adenylate cyclase. Evidence is presented that the frequent association of MSL with alcoholism is on the basis of an additional ethanol-induced membrane lesion involving β-adrenergic receptors.