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Abstract Background Estimating real-world vaccine effectiveness is challenging as a variety of population factors can impact vaccine effectiveness. We aimed to assess the population-level reduction in cumulative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases, hospitalizations, and mortality due to the BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccination campaign in Israel during January–February 2021. Methods A susceptible-infected-recovered/removed (SIR) model and a Dynamic Survival Analysis (DSA) statistical approach were used. Daily counts of individuals who tested positive and of vaccine doses administered, obtained from the Israeli Ministry of Health, were used to calibrate the model. The model was parameterized using values derived from a previous phase of the pandemic during which similar lockdown and other preventive measures were implemented in order to take into account the effect of these prevention measures on COVID-19 spread. Results Our model predicted for the total population a reduction of 648 585 SARS-CoV-2 cases (75% confidence interval [CI], 25 877–1 396 963) during the first 2 months of the vaccination campaign. The number of averted hospitalizations for moderate to severe conditions was 16 101 (75% CI, 2010–33 035), and reduction of death was estimated at 5123 (75% CI, 388–10 815) fatalities. Among children aged 0–19 years, we estimated a reduction of 163 436 (75% CI, 0–433 233) SARS-CoV-2 cases, which we consider to be an indirect effect of the vaccine. Conclusions Our results suggest that the rapid vaccination campaign prevented hundreds of thousands of new cases as well as thousands of hospitalizations and fatalities and has probably averted a major health care crisis.