The purpose of this study was to investigate how healthy young subjects with one of three variants of the brain-derived neurotrophic factor (BDNF) gene modulate motor cortex excitability following experimentally induced and use-dependent plasticity interventions. Electromyographic recordings were obtained from the right first dorsal interosseous (FDI) muscle of 12 Val/Val, ten Val/Met and seven Met/Met genotypes (aged 18–39 years). Transcranial magnetic stimulation of the left hemisphere was used to assess changes in FDI motor-evoked potentials (MEPs) following three separate interventions involving paired associative stimulation, a simple ballistic task and complex visuomotor tracking task using the index finger. Val/Val subjects increased FDI MEPs following all interventions (≥ 25%, P < 0.01), whereas the Met allele carriers only showed increased MEPs after the simple motor task (≥ 26%, P < 0.01). In contrast to the simple motor task, there was no significant change in MEPs for the Val/Met subjects (7%, P = 0.50) and a reduction in MEPs for the Met/Met group (−38%, P < 0.01) following the complex motor task. Despite these differences in use-dependent plasticity, the performance of both motor tasks was not different between BDNF genotypes. We conclude that modulation of motor cortex excitability is strongly influenced by the BDNF polymorphism, with the greatest differences observed for the complex motor task. We also found unique motor cortex plasticity in the rarest form of the BDNF polymorphism (Met/Met subjects), which may have implications for functional recovery after disease or injury to the nervous system in these individuals.