As the body of evidence on COVID-19 and post-vaccination outcomes continues to expand, this analysis sought to evaluate the public health impact of the Pfizer-BioNTech COVID-19 Vaccine, BNT162b2, during the first year of its rollout in the US. A combined Markov decision tree model compared clinical and economic outcomes of the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) versus no vaccination in individuals aged ≥12 years. Age-stratified epidemiological, clinical, economic, and humanistic parameters were derived from existing data and published literature. Scenario analysis explored the impact of using lower and upper bounds of parameters on the results. The health benefits were estimated as the number of COVID-19 symptomatic cases, hospitalizations and deaths averted, and Quality Adjusted Life Years (QALYs) saved. The economic benefits were estimated as the amount of healthcare and societal cost savings associated with the vaccine-preventable health outcomes. It was estimated that, in 2021, the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) contributed to averting almost 9 million symptomatic cases, close to 700,000 hospitalizations, and over 110,000 deaths, resulting in an estimated $30.4 billion direct healthcare cost savings, $43.7 billion indirect cost savings related to productivity loss, as well as discounted gains of 1.1 million QALYs. Scenario analyses showed that these results were robust; the use of alternative plausible ranges of parameters did not change the interpretation of the findings. The Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) contributed to generate substantial public health impact and vaccine-preventable cost savings in the first year of its rollout in the US. The vaccine was estimated to prevent millions of COVID-19 symptomatic cases and thousands of hospitalizations and deaths, and these averted outcomes translated into cost-savings in the billions of US dollars and thousands of QALYs saved. As only direct impacts of vaccination were considered, these estimates may be conservative. Why was this study done? Vaccination against COVID-19 is a crucial part of the public health response to the pandemic. The first vaccine against COVID-19 to be rolled out in the US was the Pfizer-BioNTech vaccine (also called Comirnaty or BNT162b2). In this study, we investigated how the BNT162b2 vaccine affected US public health and the economy in 2021, the first year of its use. Vaccination against COVID-19 is a crucial part of the public health response to the pandemic. The first vaccine against COVID-19 to be rolled out in the US was the Pfizer-BioNTech vaccine (also called Comirnaty or BNT162b2). In this study, we investigated how the BNT162b2 vaccine affected US public health and the economy in 2021, the first year of its use. What did the researchers do and find? We developed a mathematical model and populated it with published data on COVID-19 to estimate the benefits of receiving 2 BNT162b2 vaccine doses versus receiving no vaccination, in people 12 years and older.Vaccination against COVID-19 is a crucial part of the public health response to the pandemic. The first vaccine against COVID-19 to be rolled out in the US was the Pfizer-BioNTech vaccine (also called Comirnaty or BNT162b2). In this study, we investigated how the BNT162b2 vaccine affected US public health and the economy in 2021, the first year of its use.We estimated that the BNT162b2 vaccine helped prevent around 8.7 million symptomatic COVID-19 illnesses. We also estimated that the vaccine prevented almost 700,000 COVID-19–associated hospitalizations, and more than 110,000 deaths. We estimated that it saved around $30 billion on healthcare costs and $44 billion related to people being unable to work due to illness. Sensitivity and scenario analyses showed that, although changing the model parameters did affect the results, this did not alter the overall conclusion that the vaccine leads to favorable and substantial public health impact.This study did not include estimates for children under 12 years old, or research the benefits of a booster. We cannot assume the results would be the same for other COVID-19 vaccines. This study also did not account for the Omicron variant, which did not emerge until late in 2021. We developed a mathematical model and populated it with published data on COVID-19 to estimate the benefits of receiving 2 BNT162b2 vaccine doses versus receiving no vaccination, in people 12 years and older. Vaccination against COVID-19 is a crucial part of the public health response to the pandemic. The first vaccine against COVID-19 to be rolled out in the US was the Pfizer-BioNTech vaccine (also called Comirnaty or BNT162b2). In this study, we investigated how the BNT162b2 vaccine affected US public health and the economy in 2021, the first year of its use. We estimated that the BNT162b2 vaccine helped prevent around 8.7 million symptomatic COVID-19 illnesses. We also estimated that the vaccine prevented almost 700,000 COVID-19–associated hospitalizations, and more than 110,000 deaths. We estimated that it saved around $30 billion on healthcare costs and $44 billion related to people being unable to work due to illness. Sensitivity and scenario analyses showed that, although changing the model parameters did affect the results, this did not alter the overall conclusion that the vaccine leads to favorable and substantial public health impact. This study did not include estimates for children under 12 years old, or research the benefits of a booster. We cannot assume the results would be the same for other COVID-19 vaccines. This study also did not account for the Omicron variant, which did not emerge until late in 2021. What do researchers think the results mean? In the US, in 2021, the BNT162b2 COVID-19 vaccine contributed to preventing millions of people from getting symptomatic COVID-19 and saved billions of dollars. These results support recommendations for continued widespread vaccine use. In the US, in 2021, the BNT162b2 COVID-19 vaccine contributed to preventing millions of people from getting symptomatic COVID-19 and saved billions of dollars. These results support recommendations for continued widespread vaccine use.