Using transcranial magnetic stimulation, the effect of riluzole (RLZ) on cortical excitability was studied in patients with amyotrophic lateral sclerosis (ALS). Paired-pulse inhibition (PPI) and paired-pulse facilitation (PPF) were reduced. RLZ partially restored deficient PPI in the first of 4 consecutive 3-month periods of testing, but left PPF unchanged. These findings substantiate the view that attenuation of glutamate-related excitotoxicity is an important factor contributing to the beneficial effect of RLZ in ALS.