High titers of natural autoantibodies against the nerve growth factor (NGF) were detected in the sera of patients with systemic lupus erythematosus, autoimmune thyroiditis and rheumatoid arthritis. Autoantibodies to NGF from these pathological cases displayed higher avidity for NGF and a higher polyreactivity with certain cytoskeletal proteins and with DNA as compared to those from control human subjects. The biological activity, immunoglobulin composition and physiological relevance of these autoantibodies are discussed.