Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive disease caused by the degeneration of upper and lower motor neurons. The etiology of ALS is unclear, but there is evidence that loss of cortical inhibition could be related to motor neuron degeneration. We sought to determine whether cathodal transcranial direct current stimulation (tDCS) can reduce cortical excitability in patients with ALS. Methods: Three sessions of cathodal tDCS, lasting 7, 11, or 15 minutes, were performed in 10 patients and 10 healthy controls. Corticospinal excitability was measured before and after the tDCS. Results: Cathodal tDCS induced a consistent decrease in corticospinal excitability in healthy controls, but not in ALS patients. Conclusions: The failure of tDCS to produce an excitability shift in the patients supports the potential diagnostic value of tDCS as a marker of upper motor neuron involvement. However, variation in corticospinal excitability measurements both inter- and intraindividually will limit its usefulness. © 2011 Wiley Periodicals, Inc.