Immunoglobulins from patients with diabetic neuropathy are toxic to neuroblastoma cells. The cell death has characteristics of apoptosis: condensed chromatin, shrunken cytoplasm, elevation of [Ca2+]i and DNA fragmentation. N1E-115 cell membranes contain Fas, a regulator of apoptosis that recently has been shown to be involved in pancreatic beta-cell destruction leading to diabetes. Fas-specific antibodies bind to the surface of N1E-115 cells and induce apoptosis. Serum from patients with diabetic neuropathy block Fas-antibody binding. We conclude that sera from patients with diabetic neuropathy contain an activator of Fas-regulated apoptosis that may contribute to the pathogenesis of diabetic neuropathy.