Activated T lymphocytes and macrophages play a putative role in the the pathogenesis of Guillain-Barré syndrome. Both cell types secrete tumor necrosis factor-alpha, a cytokine that has well-recognized toxic effects on myelin, Schwann cells, and endothelial cells. We determined serum and cerebrospinal fluid concentrations of tumor necrosis factor alpha in 26 patients with Guillain-Barré syndrome, 27 patients with other polyneuropathies, 30 patients with neurological diseases of the central nervous system, and 14 healthy control subjects. Markedly increased serum levels were detected in 14 patients (54%) with Guillain-Barré syndrome and to a significantly lesser extent, in patients with other polyneuropathies (26%) and in neurological control subjects (23%). Tumor necrosis factor-alpha was not detected in the cerebrospinal fluid of patients with Guillain-Barré syndrome or other polyneuropathies. Increased serum concentrations in patients with Guillain-Barré syndrome correlated directly with disease severity and these concentrations returned to normal in parallel with clinical recovery. These findings emphasize the complexity of the immune response in patients with Guillain-Barré syndrome and suggest that tumor necrosis factor-alpha may be important in the pathogenesis of peripheral demyelination in this disorder.