Multifocal acquired demyelinating sensory and motor neuropathies are considered autoimmune and responsive to immunotherapy. In the absence of demyelination, however, they are considered idiopathic if no other cause is found. To determine whether patients with multifocal acquired sensory and motor neuropathy of an otherwise unknown cause have antiganglioside antibodies, regardless of whether they are classified as demyelinating or axonal, indicating a possible immune-mediated origin. Serum samples from 25 patients with multifocal acquired sensory and motor neuropathy of an otherwise unknown cause were tested for antibodies to gangliosides using an agglutination immunoassay. Reactive serum samples were further tested by enzyme-linked immunosorbent assay against individual gangliosides. Electrophysiologic studies were reviewed for evidence of demyelination. Increased levels of ganglioside antibodies were detected in 12 (48%) of the 25 patients using the agglutination immunoassay, and in 7 (58%) of the 12 agglutination-positive patients by the enzyme-linked immunosorbent assay. Serum samples from these 7 patients had IgG antibodies to 1 or more gangliosides; none had elevated levels of IgM antiganglioside antibodies. Three of the patients fulfilled 2 of the American Academy of Neurology electrophysiologic criteria for demyelination, but none fulfilled the 3 of the 4 possible criteria required for the diagnosis of demyelinating neuropathy. A sural nerve biopsy specimen in 2 patients revealed axonal degeneration. Multifocal sensory and motor neuropathies of an otherwise unknown cause may be associated with antiganglioside antibodies, regardless of whether they exhibit demyelinating features.