Antibodies against acetylcholinesterase were found in the serum of a patient presenting dyspnea, generalized muscle paresis, diminished tendon reflexes, and fasciculations. Electrodiagnostic studies showed a decremental response, an incomplete interference pattern, and reduced motor nerve conduction velocity. Edrophonium administration resulted in extreme cholinergic crisis. Biopsies displayed muscle atrophy and nervous tissue degeneration. Recurrent acute respiratory failure ended in death. The patient's serum pseudocholinesterase and red blood cells acetylcholinesterase levels were generally very low, with periodical fluctuations. Minute quantities of the patient's serum inhibited the activity of cholinesterases from normal human serum and from various fetal tissues. Enzyme inhibition was abolished following preadsorption of the serum immunoglobulins with goat antihuman Fab, and radioiodinated acetylcholinesterase from human erythrocytes was precipitated by the patient's serum, confirming that anticholinesterase antibodies were present. Acetylcholinesterase extracted from fetal striated muscle with detergent and salt was inhibited to a larger extent than the enzymes similarly prepared from other fetal tissues and more efficiently than buffer-soluble muscle enzyme. These findings suggest that the patient's serum contained antibodies which interacted preferentially with the membrane-associated forms of muscle acetylcholinesterase and indicate that autoantibodies against acetylcholinesterase could play a role in the pathogenesis of the disease.