<b><i>Background:</i></b> Older adults living in long-term care facilities (LTCFs) are at increased risk for severe outcomes from COVID-19 and were identified as a priority group in COVID-19 vaccination strategies. Emerging evidence suggests vaccine effectiveness in LTCF populations, but data about median and long-term durability of immune response after vaccination are still limited. <b><i>Objectives:</i></b> In this study, we assessed the humoral response to BNT162b2 mRNA COVID-19 vaccine 3 months after the second dose, in a cohort of 495 residents aged ≥65 years from 11 LTCF in Granada, Spain. <b><i>Method:</i></b> Between April 19 and April 30, 2021, we measured anti-SARS-CoV-2 Spike IgG to evaluate the humoral vaccination response. Antibody titers were reported in binding antibody units (BAU/mL). Bivariate and multivariate logistic regression models were performed to investigate the impact of age, sex, underlying health conditions, and prior COVID-19 infection on the antibody levels. <b><i>Results:</i></b> Over 96% of the participants developed an adequate humoral response. We detected higher antibody titers in previously infected individuals, compared with those previously uninfected (<i>B</i>: 1,150.059 BAU/mL, <i>p</i> &#x3c; 0.001). Moreover, we found a significant inverse association between age and antibody levels (<i>B</i>: −7.943 BAU/mL, <i>p</i> &#x3c; 0.05). This negative age-dependent response was more noticeable among residents over 85 years old. In contrast, baseline health conditions and cognitive status were not associated with different antibody levels. <b><i>Conclusions:</i></b> These findings support monitoring COVID-19 vaccination response trend in older adults, in order to optimize future disease prevention and control strategies in this vulnerable population.

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