The serum of patients with Lyme neurologic disease contain antibodies that bind to human axonal antigens that cross-react with Borrelia burgdorferi. The sera also bind to SK-N-SH neuroblastoma cells, especially the neuritic processes of these cells. H9724, a murine IgG monoclonal antibody to B. burgdorferi flagellin, binds to an SK-N-SH cell protein of approximately 64,000 apparent molecular weight (M(r)). H9724 immunoprecipitates a protein of the same M(r) (p64) from the cells and from a delipidated preparation of human peripheral nerve. The Lyme disease patient sera that bind to human axons and SK-N-SH cells also bind to the immunoprecipitated p64. Immunologic cross-reactivity between borrelial and human axonal proteins may be involved in the immunopathogenesis of Lyme neurologic disease.