Sera and cerebrospinal fluid (CSF) from 25 patients with amyotrophic lateral sclerosis (ALS) were tested by immunofluorescence on fetal, juvenile and adult central and peripheral neuronal (CNS/PNS) tissues and on nerve biopsy material from affected patients for the presence of autoantibodies. Results were compared with control sera from normal blood donors (n = 45) and patients with other neurological diseases (OND) (n = 11). Three different types of tissue reactivity (glial, axonal, and small blood vessels) were found. Antibodies binding to glial and axonal structures were found in 32% of ALS patients as compared to 12% in normal and 27% in OND controls. In contrast, staining of endothelial cells was found with 24% of ALS sera and CSF but not with normal and OND control sera and was demonstrated only with fetal and juvenile nervous tissue and with suralis nerve biopsies of two of five ALS patients. However, normal or inflamed adult CNS/PNS tissue was not stained with these sera. We conclude that ALS is most likely a heterogeneous group of diseases and only a subgroup of ALS may have an autoimmune pathogenesis. These findings may, therefore, have implications for the evaluation of any immunosuppressive treatment in ALS.