Plasticity of synaptic connections in the primary motor cortex (M1) is thought to play an essential role in learning and memory. Human and animal studies have shown that motor learning results in long-term potentiation (LTP)-like plasticity processes, namely potentiation of M1 and a temporary occlusion of additional LTP-like plasticity. Moreover, biochemical processes essential for LTP are also crucial for certain types of motor learning and memory. Thus, it has been speculated that the occlusion of LTP-like plasticity after learning, indicative of how much LTP was used to learn, is essential for retention. Here we provide supporting evidence of it in humans. Induction of LTP-like plasticity can be abolished using a depotentiation protocol (DePo) consisting of brief continuous theta burst stimulation. We used transcranial magnetic stimulation to assess whether application of DePo over M1 after motor learning affected (1) occlusion of LTP-like plasticity and (2) retention of motor skill learning. We found that the magnitude of motor memory retention is proportional to the magnitude of occlusion of LTP-like plasticity. Moreover, DePo stimulation over M1, but not over a control site, reversed the occlusion of LTP-like plasticity induced by motor learning and disrupted skill retention relative to control subjects. Altogether, these results provide evidence of a link between occlusion of LTP-like plasticity and retention and that this measure could be used as a biomarker to predict retention. Importantly, attempts to reverse the occlusion of LTP-like plasticity after motor learning comes with the cost of reducing retention of motor learning.