Sera from 64 patients with the Lambert-Eaton myasthenic syndrome (LES) were tested for evidence of autoimmunity to a variety of tissue antigens. One or more organ-specific autoantibodies (thyroid, gastric, and/or skeletal muscle) were found in 29 patients (45%). Of 46 patients without evidence of tumor, autoantibodies were found in 24 (52%), and of 18 patients with tumor, autoantibodies were found in 5 (28%). In an age-matched group of 40 patients with miscellaneous neurologic diseases, 7 (17%) had one or more organ-specific autoantibodies, and in a control group of 47 patients with myasthenia gravis the combined prevalence of thyroid and gastric antibodies was 47%, comparable to that found in LES patients. The prevalence of non-organ-specific autoantibodies (for example, rheumatoid factor and/or antinuclear antibodies) was not significantly elevated in LES. These data clearly justify consideration of LES without tumor as an organ-specific autoimmune disease. If LES with tumor does prove to have an autoimmune basis, the mechanism may involve an antigen common to cholinergic neurons and oat cell carcinoma, both of which are neuroectoderm derivatives.