Response to pharmacological treatments is moderated by both genetic and environmental factors. The contribution of such factors is relatively small and complex interactions are likely to be involved. Serotonin transporter gene (SLC6A4) is a major candidate gene associated to response to antidepressant treatment. Moreover, the 5-HTTLPR polymorphism has been associated with anxiety-related traits such as neuroticism and harm avoidance (HA), which are known to influence the risk to develop mood disorders and response to treatments. In the present study we aimed to investigate the interaction between 3 SLC6A4 variants and HA on medium term antidepressant response in a sample of depressed bipolar-spectrum patients followed for 12 months. Contrary to expectations, SLC6A4 variants did significantly influence neither the course of depressive symptoms nor HA scores. However, a significant interaction was observed between HA and 5-HTTLPR genotype. Indeed, a high HA impaired outcome in patients carrying the L(G)/S or the S/S genotype more than in L(A)/L(A) patients. Though a number of limitations characterize the present study, our results indicate HA as a potential moderator of the effect of 5-HTTLPR on the outcome of depression. Given that many factors may influence response to pharmacological treatments, studies that consider personality and other individual characteristics are warranted also in pharmacogenetic investigations.