Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is widely regarded as an autoimmune disorder, although the autoantigen remains unknown. In this study, the sera of 21 CIDP patients were examined by immunofluorescence for antimyelin activity and by Western blotting for binding to myelin proteins. Six sera contained anti-P0 immunoglobulin G antibodies, and four of these caused conduction block and demyelination following intraneural injection in experimental animals. Absorption with P0 protein eliminated the demyelinating activity. These results show that P0 is an autoantigen in some patients with CIDP. Since P0 possesses powerful adhesion properties and is largely responsible for myelin compaction, the demonstration of demyelination by human anti-P0 antibodies provides new insight into this important and common immunopathological process.