Background <p>The ageing population faces numerous physiological changes, among which immunosenescence plays a central role. Understanding the mechanisms underlying immunosenescence remains a priority. Within this framework, the contribution of comorbidities to immune dysfunction is still poorly characterized, despite growing evidence suggesting that it may represent a critical determinant in the evaluation of immunosenescence. The main objective of this report was to disentangle the respective impacts of age and comorbidities. To this end, we focused on immunological parameters originally developed in the context of sepsis, a condition that shares many immunological defects with immunosenescence.</p> Methods <p>Data were obtained from two cohorts: the REALISM cohort, including healthy elderly individuals, and the SENIOR-HLA-DR cohort, consisting of a real-life hospitalized geriatric population. Immunological parameters assessed were circulating IL-6, percentage of immature neutrophils, monocyte HLA-DR expression (mHLA-DR), neutrophil-to-lymphocyte ratio (NLR), T lymphocyte count, and interferon-γ release assay (IGRA) in response to phytohemagglutinin (PHA).</p> Results <p>In the absence of comorbidities, age had no detectable effect on immune parameters in the REALISM cohort (<i>n</i> = 174 individuals). The SENIOR-HLA-DR cohort (<i>n</i> = 76 patients) revealed that cardiovascular comorbidities exerted the greatest influence, being associated with significantly reduced mHLA-DR expression and increased NLR. Infections further triggered substantial alterations in inflammation and innate immunity, characterized by elevated percentages of immature neutrophils and decreased mHLA-DR expression.</p> Discussion-Conclusions <p>Our findings indicate a limited impact of chronological age and comorbidities on the selected immunological parameters. These results suggest that routine clinical tools may be insufficient to fully capture the complexity of immunosenescence.</p>