Long-term care facilities (LTCFs) have been severely impacted by COVID-19, with a disproportionate amount of SARS-CoV-2 infections and related deaths occurring among residents. This study is part of an ongoing multicenter, prospective cohort study conducted among healthcare workers(HCWs) and residents of 13 LTCFs in Northern Italy designed to evaluate SARS-CoV-2 specific immunoglobulin class G (IgG) titers before and following vaccination with Pfizer/BNT162b2 SARS-CoV-2 mRNA vaccine (two doses of vaccine, 21 days apart). Serum samples were obtained from participants (t0) before vaccination, and (t1) 2 weeks after and analyzed to determine anti-S1 IgG antibodies. Five hundred and thirty-fourparticipants were enrolled (404 subjects participated in both blood draws). Seropositivity was 50.19% at t0and 99% at t1, with a significant difference in IgG titers. A higher proportion of residents were seropositive at t0 compared withHCWs, with significantly higher IgG titers among residents at both t0 and t1. Pre-existing immunity also had a significant effect on postvaccination IgG titers. However, a significant difference in titers at t1 between HCWsand residents considering only participants seropositive at t0 was found, with higher median titers among previously seropositive residents. Findings of this study provide scientific evidence endorsing the policy of universal vaccination in LTCFs.