Depression and cognitive decline have been associated with changes in circulating cortisol concentrations. Cortisol exerts its functions through mineralocorticoid (MR) and glucocorticoid (GR) receptors. However, data on the influence of variations in the MR and GR genes on depressive symptoms and cognitive functioning in older adults are scarce. Therefore, we explored the impact of MR-215G/C, MR-I180V, GR-ER22/23EK, GR-N363S, and GR-BclI polymorphisms on these end points in the population-based Leiden 85-plus Study. This prospective study includes 563 participants aged 85 years and older, with a mean follow-up of 4.2 years. In this study, high morning cortisol levels (per 1 SD cortisol) associated with impairments in global cognitive functioning (p=0.002) at baseline (age 85). These impairments were mainly attributable to lower attention (p=0.057) and slower processing speed (p=0.014). Similar effects were also observed during follow-up (age 85-90), where participants with higher cortisol levels (per 1 SD cortisol) had impaired global cognitive functioning (p=0.003), as well as impairments in attention (p=0.034) and processing speed (p=0.013). Changes in depressive symptoms were observed for the MR-I180V single-nucleotide polymorphism (SNP), where during follow-up the prevalence of depressive symptoms was higher in the 180V-allele carriers (p=0.049) compared to noncarriers. Dependent on these polymorphisms, no differences in overall and in specific domains of cognitive functioning were observed. In conclusion, the MR-I180V SNP has a specific effect on depressive symptoms, independent from cognitive functioning, and other polymorphisms in the MR and GR genes. In contrast, these genetic variants in the MR and GR genes do not influence cognitive functioning in old age.