Background: Motor cortex stimulation has been proposed for treatment of amyotrophic lateral sclerosis (ALS) and preliminary studies have reported a slight reduction of disease progression using both invasive and noninvasive repetitive stimulation of the motor cortex. Objective: The aim of this proof of principle study was to investigate the effects of motor cortex stimulation performed for a prolonged period (about 2 years) on ALS progression. Methods: Two patients were included in the study; the first patient was treated with monthly cycles of repetitive transcranial magnetic stimulation (rTMS) and the second one was treated with chronic epidural motor cortex stimulation. The rate of progression of the disease before and during treatment was compared. Results: The treatments were well tolerated by the patients. Both patients deteriorated during treatment; however, the patient treated with rTMS showed a slight reduction in deterioration rate. Conclusions: Although we cannot be sure whether the effects observed in the patient treated with rTMS can be attributed to this form of stimulation, our study set the groundwork for possible future studies investigating the effects of rTMS, for a prolonged period, on a larger group of ALS patients. © 2010 Elsevier Inc. All rights reserved.