BACKGROUND: Mixed evidence in the general population and medically ill patients has suggested that homozygous carriers of the short allele (s/s) of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may increase the risk of depression in comparison with carriers of the long allele (l/l) or s/l. Given the lack of data in oncology, we examined the relationship of depression with the 5-HTTLPR and psychosocial variables among breast cancer patients. METHODS: A sample of 145 breast cancer patients were studied as regards to depression, psychosocial-related variables (coping, Type D-personality, life events, and social support), and the 5-HTTLPR, which was genotyped by using a standard protocol with DNA extracted from the blood. RESULTS: No difference was found between s/s, s/l and l/l patients on depression and any other psychosocial variable. No gene-by environment (GxE) interactions were observed between the 5-HTTLPR and recent life events. CONCLUSIONS: The study did not provide support of a possible association between 5-HTTLPR polymorphism, alone or in conjunction with life events, and depression in newly diagnosed breast cancer. Further follow-up studies are however necessary to confirm these data.