Background: Elderly people are exposed to an increased load of stressful events and neuro-hormonal stimulation is a key finding in metabolic syndrome and its related disorders. Aims: To determine the role of cortisol in elderly subjects, with or without metabolic syndrome (MetS), by means of a national multicentre observational study, AGICO (AGIng and Cortisol). Methods: From 2012 to 2017, the AGICO study enrolled n.339 subjects (aged > 65), after obtaining their informed consent. The investigators assessed a cardio-metabolic panel (including electrocardiogram, carotid ultrasonography and echocardiography), the presence of MetS (on Adult Treatment Panel III criteria), a neurological examination (including brain imaging), and cortisol activity (using a consecutive collection of diurnal and nocturnal urine). Results: In the patients presenting with MetS, the standardized diurnal and nocturnal cortisol excretion rates were 210.7 ± 145.5 and 173.7 ± 118.1 (mean ± standard deviation) μg/g creatinine/12 h; in those without MetS, the standardized diurnal and nocturnal cortisol excretion rates were 188.7 ± 92.7 and 144.1 ± 82.3 μg/g creatinine/12 h, respectively (nocturnal urinary cortisol in patients with MetS versus those without MetS p = 0.05, female patients with MetS vs female patients without MetS, p < 0.025). A significant positive correlation was found between the CRP levels and both the diurnal and nocturnal urinary cortisol levels with r = 0.187 (p < 0.025) and r = 0.411 (p < 0.00000001), respectively. Discussion: The elderly patients with MetS showed a trend towards increased standardized nocturnal cortisol excretions, with particular regard to the female subjects. Conclusion: The positive correlation between cortisol excretion and low-grade inflammation suggests a common mechanism driving both hormonal and inflammatory changes.