Introduction: Learning may alter rapidly the output organization of adult motor cortex. Long-term potentiation (LTP) and long-term depression (LTD) form important mechanisms for learning-induced cortical plasticity. Evidence in favour of this hypothesis was provided in rat primary motor cortex (M1) by showing that motor learning reduced the subsequent induction of LTP but increased LTD (Rioult-Pedotti et al. 2000). Whether a similar relationship exists in humans is unknown. Methods: We induced LTP-like and LTD-like plasticity in the M1 of 12 healthy subjects by paired associative stimulation (PAS) (Stefan et al. 2000). PAS consisted of 200 pairs of electrical stimulation of the right median nerve followed by focal TMS of the hand area of the left M1 at an interval equalling the individual N20 latency of the median nerve somatosensory evoked cortical potential (PASN20) or N20 – 5 ms (PASN20-5). Results: PASN20 induced reliably an LTP-like long-lasting (> 30 min) increase in motor evoked potentials from the left M1 to a thumb abductor muscle of the right hand, whereas PASN20-5 induced a LTD-like decrease. Repeated fastest possible thumb abduction movements resulted in learning, defined by an increase in maximum peak acceleration of the practiced movements. Learning prevented the subsequent induction of LTP-like plasticity by PASN20, but enhanced the induction of LTD-like plasticity by PASN20-5. Further experiments showed that LTD-like plasticity enhanced subsequent motor learning. Conclusions: Findings strongly support the contention that learning in human M1 occurs through LTP-like mechanisms. The interactions between learning and LTP/D-like plasticity are best explained by the Bienenstock-Munroe-Cooper theory (Bienenstock et al. 1982) of bi-directional synaptic plasticity.