Background: Aging is related to changes in functional reserve that progressively lead to increased morbidity and mortality. Frailty syndrome, a common entity in older adults, is characterized by increased vulnerability to stress secondary to a decline in homeostasis caused by dysregulation. Objective: The study aimed to evaluate the immunocompetence of elderly individuals with frailty syndrome. Methods: A cross-sectional and translational study was carried with sixty-nine older adults with frailty syndrome (patients) and 42 healthy older adults (controls) were included. Results: Low naive TCD4+ cells (P = 0.03) in patients with Frailty syndrome compared to controls. Low levels of total T cells (P = 0.01), TCD4+ (P = 0.005), and TCD4+/TCD8+ ratio (P = 0.04), memory T cells (P = 0.02), memory TCD4+ (P = 0.001), memory T CD8+ (P < 0.0001), and high levels of naïve/memory T cells ratio (p = 0.008) in Frailty syndrome patients with age ≥70 years. Conclusion: Older adults with frailty syndrome have alterations in the cellular immune response, and these findings may be associated with increased morbidity and mortality in these patients.