Given the increasing prevalence of psychiatric disorders, expanding our knowledge of the environmental and genetic contributions to risk-related vulnerability to psychiatric disease is of utmost importance. In the present study, we examined gene polymorphisms of brain-derived neurotrophic factor (BDNF), a contributor to brain plasticity, and tryptophan hydroxylase 2 (TPH2), a brain-specific rate-limiting enzyme in the production of serotonin, for their interactive roles in emotional regulation. The BDNF polymorphism involves a single nucleotide polymorphism (SNP) within the prodomain coding region of the gene, resulting in a methionine (Met) substitution for valine (Val) at codon 66. The SNP examined within the TPH2 gene involves a T substitution for a G in the non-coding regulatory region of the gene affecting transcriptional activity. Saliva was collected for DNA analysis from participants shown a series of well-validated emotion-evoking films (study 1), or given an emotion word Stroop task (study 2). Results revealed two high risk populations; participants homozygous for BDNF Val in combination with TPH2 G/G, and BDNF Met carriers in combination with TPH2 T carriers. Both of these genotype combinations exhibited significantly greater impairments in inhibiting negative emotional content. The present study provides evidence of epistatic relationships between BDNF and TPH2 on emotional regulation, and demonstrates the importance of studying genetic influences on emotion regulation. Together, these findings suggest that both risk groups have poor emotion-inhibitory responses that may leave them vulnerable for the most common emotion-related psychiatric disorders.