Although chronic inflammatory demyelinating polyneuropathy (CIDP) is presumed to be an autoimmune disorder, no neural antigen has been recognized as an immune target. We found that serum IgM from a patient with CIDP and an IgM paraprotein reacted with a 53-kd protein by Western blot analysis. Amino acid sequence analysis identified this protein as β-tubulin. We then studied sera from 70 CIDP patients, 35 Guillain-Barré syndrome (GBS) patients, and 483 disease (amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis, diabetes, and other polyneuropathies) and normal controls for selective high-titer anti-β-tubulin using ELISA methodology. Forty-two percent (30/70) of patients with CIDP had selective high titer IgM reactivity against β-tubulin; 23% (16/70) had selective high-titer IgG reactivity against β-tubulin. Overall, 57% of CIDP patients, 20% of GBS patients, and 2% of control patients had selective, high serum IgM or IgG anti-β-tubulin reactivity. Selective high-titer serum anti-β-tubulin antibodies occur in a majority of patients with CIDP but are rare in other chronic neuropathies or CNS disorders.