<b><i>Introduction:</i></b> In early 2020, the novel SARS-CoV-2 virus began to spread around the world and claim victims. Initially, in the Western world, COVID-19-related mortality was due to illness in long-term care facilities (LTCFs). To manage the COVID-19 crisis in LTCFs in Israel, the Ministry of Health established a task force named “Senior Shield.” The task force executed a screening program of weekly polymerase chain reaction (PCR) SARS-CoV-2 tests for LTCF residents and caregivers, and at a later stage, the task force led the Ministry of Health vaccination program at LTCFs. This study aimed to estimate the effectiveness of the BNT162b2 mRNA COVID-19 (Comirnaty) vaccine in reducing COVID-19 morbidity and mortality in LTCF residents. <b><i>Methods:</i></b> We designed a nationwide cohort study utilizing data from the Senior Shield task force. Residents had received the vaccines starting December 2020. The study follow-up period was 5 months (ending May 2021). We defined four outcomes: (a) documented SARS-CoV-2 infection, defined by a positive PCR test, (b) COVID-19 death, defined by a positive PCR test followed by death, (c) all-cause mortality, defined as death regardless of the result of a PCR test, and (d) a composite endpoint which included documented SARS-CoV-2 infection or death, the earliest of both. We used Kaplan-Meier curves with a log-rank comparison and Cox regression with a time-dependent covariate model to estimate adjusted hazard ratios for vaccine effectiveness (VE). The index date was the date of the first vaccine dose. In unvaccinated residents, the index date was the first date of vaccination in their LTCF. <b><i>Results:</i></b> A total of 43,596 residents with a mean age of 83 years living in 454 LTCFs were found eligible for this study. Ninety-one percent of the study population received the first vaccine dose (39,482) and 86% received the second vaccine dose (37,656). Estimated VE 28 days after the first vaccine dose (approximately 7 days after the second vaccine dose) was 81.2% for SARS-CoV-2 infection, 85.3% for COVID-related death, 63.7% for all-cause mortality, and 71.1% for the composite endpoint (SARS-CoV-2 infection or death). <b><i>Conclusion:</i></b> This study shows that the BNT162b2 mRNA COVID-19 vaccine effectively prevents SARS-CoV-2 infection, COVID-19-related death, and all-cause mortality in LTCF residents. Further research is warranted on the effect of the third vaccine (booster) in this population.