The common single-nucleotide polymorphism (SNP) brain-derived neurotrophic factor (BDNF) valine-to-methionine substitution at codon 66 (Val66Met) has been associated with differences in memory functions and cortical plasticity following brain stimulation. Other studies could not confirm these results, though, and potential interactions of BDNF carrier status with other learning-relevant SNPs are largely unknown. The present study aimed to evaluate the effects of BDNF Val66Met genotype on paired associative stimulation (PAS)-induced motor cortex plasticity, while additionally taking catechol-O-methyltransferase (COMT) Val158Met and kidney and brain (KIBRA) rs17070145 carrier status into account. Therefore, a cohort of 2 × 16 age- and education-matched healthy young females underwent transcranial magnetic stimulation using an excitatory PAS(25) protocol to induce cortical plasticity. Cognitive performance was assessed using implicit grammar- and motor-learning tasks and a detailed neuropsychological test battery. While BDNF carrier status alone did not significantly influence PAS-induced cortical plasticity, we found a significant BDNF × COMT interaction, showing higher plasticity immediately following the PAS(25) protocol for the BDNF Val/Val vs Met genotype in COMT Met homozygotes only (ANOVA, p = 0.027). A similar advantage for this group was noted for implicit grammar learning (ANOVA, p = 0.021). Accounting for KIBRA rs17070145 did not explain significant variance. Our findings for the first time demonstrate an interaction of BDNF by COMT on human cortical plasticity. Moreover, they show that genotype-related differences in neurophysiology translate into behavioral differences. These findings might contribute to a better understanding of the mechanisms of interindividual differences in cognition.