Previous experiments in slice preparations revealed that pharmacological activation of GABAB receptors down- or up-regulates long-term potentiation (LTP), depending on whether increase of GABAB receptor mediated inhibitory postsynaptic potentials or decrease of presynaptic auto-inhibition of GABAA receptor mediated inhibition predominates. The effects of GABAB receptor activation on LTP in humans in vivo are unknown. Here we show, by using transcranial magnetic stimulation, that the GABAB receptor agonist baclofen decreases paired associative stimulation induced LTP-like plasticity in human motor cortex. This suggests that increased GABAB mediated inhibitory postsynaptic potentials drive this effect, and that baclofen may have a negative impact on LTP-dependent behavioural processes such as motor learning.