While GABA(B) receptors are thought to have an important role in mediating long interval intracortical inhibition (LICI) in the human motor cortex, the effect of a selective GABA(B) receptor agonist on this measure has not been directly tested. Nine healthy volunteers ingested either 50 mg baclofen (BAC) or placebo (PBO) in a randomized, double blind crossover design, with the second session one week later. We used transcranial magnetic stimulation to assess motor threshold, motor evoked potential (MEP) amplitude, cortical silent period (CSP) duration, short interval intracortical inhibition (SICI) and LICI before and 90 min following drug intake. There was no specific effect of drug on motor threshold, MEP amplitude or CSP duration. BAC resulted in a significant increase in LICI (P=0.002) and a significant decrease in SICI (P=0.046) while PBO had no effect. Our findings demonstrate that the enhanced GABA(B) receptor activation results in differential effects on these two measures of intracortical inhibition in the human motor cortex. The increase in LICI is likely to be a result of increased GABA(B) receptor mediated inhibitory post-synaptic potentials, while the reduction in SICI may relate to the activation of pre-synaptic GABA(B) receptors reducing GABA release.