Variability in the serotonin transporter (5-HTTLPR) gene can influence the risk of depression associated with adversity, as well as cortisol stress reactivity, although not consistently. No study has examined the impact of both a stressful environment and corticotropic-axis dysfunction on depression, as a function of 5-HTTLPR. This population-based study included 334 subjects aged 65 and older. Depression was measured at both diagnostic (major depression according to DSM-IV) and symptomatic (subthreshold depression) levels of caseness, in addition to 5-HTTLPR and rs25531 genotyping and diurnal cortisol measures. For participants with the SS genotype, higher morning cortisol levels were associated with a 4-fold increased risk of depression. Among LL participants, both evening cortisol levels and recent stressful events increased depression risk, although only the latter remained significant after multivariable adjustment. Conversely, SL individuals appeared somewhat resilient to depression in terms of cortisol and recent stress. These findings indicate that 5-HTTLPR genetic variability appears to influence the association between stress-related factors and late-life depression, although the gene-environment interactions failed to reach statistical significance levels. Participants homozygous for the short allele appeared to have a cortisol-related neuroendocrine vulnerability to depression, while long allele homozygotes were more reactive to stressful events in terms of depression risk.