Objectives. To assess the effectiveness of vaccine-induced immunity against new infections, all-cause emergency department (ED) and hospital visits, and mortality in Indiana. Methods. Combining statewide testing and immunization data with patient medical records, we matched individuals who received at least 1 dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines with individuals with previous SARS-CoV-2 infection on index date, age, gender, race/ethnicity, zip code, and clinical diagnoses. We compared the cumulative incidence of infection, all-cause ED visits, hospitalizations, and mortality. Results. We matched 267 847 pairs of individuals. Six months after the index date, the incidence of SARS-CoV-2 infection was significantly higher in vaccine recipients (6.7%) than the previously infected (2.9%). All-cause mortality in the vaccinated, however, was 37% lower than that of the previously infected. The rates of all-cause ED visits and hospitalizations were 24% and 37% lower in the vaccinated than in the previously infected. Conclusions. The significantly lower rates of all-cause ED visits, hospitalizations, and mortality in the vaccinated highlight the real-world benefits of vaccination. The data raise questions about the wisdom of reliance on natural immunity when safe and effective vaccines are available. (Am J Public Health. 2023;113(1):96-104. https://doi.org/10.2105/AJPH.2022.307112).