We have used peristimulus time histograms to study how paired, transcranial magnetic stimulation alters the firing of single motor units and the magnitude of unitary excitatory postsynaptic potentials (EPSPs) recorded from the extensor digitorum communis muscle. With stimulus intensity at threshold and an interstimulus interval of 30 ms, normal subjects (n = 20) demonstrated marked inhibition with a mean test/conditioning EPSP ratio of 13.8% (range 0-51%) and in 7 subjects the ratio was 0 (100% inhibition). In amyotrophic lateral sclerosis (ALS) the ratio was 133% (range 64-267%), P < 0.001. Fifty percent of patients had a test/conditioning EPSP ratio greater than 100% (0 inhibition). The abnormalities were independent of disease severity, bulbar versus spinal ALS, more prominent upper versus lower motor neuron findings, and disease duration. Normal inhibition occurred in 3 individuals, 1 each with multiple sclerosis, Kennedy's syndrome, and monomelic amyotrophy. We speculate that the marked loss of inhibition seen in all patients with ALS, which may be unique to this disorder, reflects loss of inhibitory modulation of the corticomotoneuron and could result in their chronic excitatory drive and eventual demise.