The ataxia-telangiectasia (A-T) syndrome consists of multiple abnormalities of the neurologic, vascular, endocrinologic and immunologic systems. Any postulate regarding the pathogenesis of the clinical syndrome must explain the multiple system involvment and account for the progressively more wide-spread and severe involvement with time. Some of the features of this syndrome might be explained if an autoimmune process were operative. 17 patients with A-T, ages 4 to 39 years, were studied for laboratory evidence of autoimmune phenomenon. The following investigations were performed: rheumatoid factor, anti-IgA antibodies, anti-deoxy-nuclocoprotein antibodies, anti-thyroglobulin antibodies and fluorescent antibodies directed against the stomach, muscle, adrenal, pituitary, ovary, testis and thymus, 12 of 17 patients demonstrated 1 or more of the above antibodies. One patient was positive for rheumatoid factor, 6 patients without serum IgA had anti-IgA antibodies, 2 had antithyroid antibodies and 2 had anti-muscle, antibodies. Especially striking was the finding of anti-IgA antibodies in 3 patients with normal serum IgA levels. 30 age-matched controls were negative for all the above tests. The fundatmental defect in A-T is probably immunologic. An altered immunologic response could lead to multiple system disease as a direct result of auto-antibody destruction. it is also possible that deficient immunity may permit an infectious agent to cause widespread tissue damage with secondary production of autoantibodies. (Supported by NIH AI-07726 and National Tuberculosis Foundtion.)