Autoimmune abnormalities have been described in sporadically acquired amyotrophic lateral sclerosis (ALS), but ALS patients do not benefit from conventional immunosuppressive therapy. Because Multifocal Motor Neuropathy causes a syndrome mimicking the lower motor neuron involvement in ALS and responds to high dose cyclophosphamide, we tested whether ALS patients would respond to the same treatment. Eighteen patients with classical ALS initially received a high loading dose of intravenous cyclophosphamide (3 g/m2) followed by 6-monthly injections of 750-1000 mg/m2. We monitored isometric strength, fine motor coordination and pulmonary function monthly for 3 months prior to the study, during the treatment phase, and for 6 months after treatment. Treatment subjects were matched to control subjects from the WALS natural history data base and compared on the basis of decline rate (megaslopes). Treatment did not alter the course of ALS.