Epistasis, the interaction between genes, is a topic of current interest in molecular and quantitative genetics. We have further studied a previously investigated sample of 187 major depressive disorder (MDD) patients, 171 bipolar disorder (BD) patients, and 288 controls, and tried to analyze the interaction between a set of variations of independent genes: the trace amine receptor 6 (rs4305745, rs8192625, rs7452939, rs6903874, and rs6937506) and the heat shock protein 70 (rs562047, rs1061581, rs2227956). The multifactor dimensionality reduction (MDR) method was applied and the covariates associated with diagnosis were also controlled. A significant predictive value of specific interactions between genotypes located in the investigated genes was found. We then report preliminary evidence that the epistasis between trace amine receptor 6 and heat shock protein 70 variations may compose a risk profile for major mood disorders. The level of statistical significance (P < 0.001) and the testing balancing accuracy over 0.62 suggest a cautious optimism toward this result, although the possibility of false positivity warrants further analyses in independent samples.