BACKGROUND : Depression following the diagnosis of breast cancer has been well documented, and occurs in as many as 40% of women. The serotonin transporter gene SLC6A4 and its functional polymorphism 5-HTTLPR have been extensively studied as factors in the development of depression. Many research studies have demonstrated conflicting results, and the contribution of 5-HTTLPR to depression is unclear. OBJECTIVE : The purpose of this study was to compare the relationship between depressive symptoms and serotonin transporter gene polymorphisms between women with early-stage breast cancer 1 year following initial diagnosis and surgery and matched controls. METHODS : Participants (N = 125), included postmenopausal women following breast cancer surgery (n = 80) and age-and education-matched healthy controls (n = 45). The genetic elements of interest were the long (LA) and short (S) alleles of 5-HTTLPR, as well as the single nucleotide polymorphism rs25531 A > G within the L-allele (LG). DNA was extracted from either blood or saliva and analyzed for the SLC6A4 polymorphisms. The outcome measures for this longitudinal study included Beck Depression Inventory scores and physical function domain scores from the Medical Outcome Study Short Form 36. RESULTS : Women with breast cancer demonstrated greater depressive symptomatology and decreased physical function compared to healthy controls. The LA/LA genotype was associated with increased depressive symptomatology in the overall sample and within the controls. The LA/LA genotype appeared with greater frequency in the experimental group, but the relationship with increased depressive symptoms was not observed. Physical function was a significant (p < 0.00) predictor of depressive symptoms in both groups at 12 months. CONCLUSIONS : The relationship between 5-HTTLPR and depressive symptomatology in breast cancer patients remains unclear. A potential clinical application includes monitoring physical function and addressing increased depressive symptoms as physical function declines.