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The immune factors associated with impaired SARS-CoV-2 vaccine response in elderly people are mostly unknown. We studied individuals older than 60 and younger than 60 years, who had been vaccinated with SARS-CoV-2 BNT162b2 mRNA, before and after the first and second dose. Aging was associated with a lower anti–RBD IgG levels and a decreased magnitude and polyfunctionality of SARS-CoV-2–specific T cell response. The dramatic decrease in thymic function in people > 60 years, which fueled alteration in T cell homeostasis, and their lower CD161+ T cell levels were associated with decreased T cell response 2 months after vaccination. Additionally, deficient DC homing, activation, and TLR-mediated function, along with a proinflammatory functional profile in monocytes, were observed in the > 60-year-old group, which was also related to lower specific T cell response after vaccination. These findings might be relevant for the improvement of the current vaccination strategies and for the development of new vaccine prototypes., This work was supported by the Consejería de Transformación Económica, Industria, Conocimiento y Universidades, Junta de Andalucía grants CV20-85418 and P20_00906 and by research contracts DOC-01659 and DOC-00963, as well as by Consejería de Salud, Junta de Andalucía research contract RH-0037-2020 and Instituto de Salud Carlos III CP19/00159, FI17/00186, FI19/00083, PI19/01127, and CM20/00243 from Fondos FEDER. ERM was supported by the Spanish Research Council (CSIC). We thank all the community volunteers, participants from the IBiS, Chema Niño, and the nursing staff from Virgen del Rocío University Hospital who have taken part in this project. We also thank Alicia Gutierrez and Esperanza Muñoz for reviewing the manuscript. In memoriam Silvio Manuel Pérez Martín.