With the emergency use authorization of multiple vaccines against SARS-CoV-2 infection, data are urgently needed to determine their effectiveness in a real-world setting.

To evaluate the short-term effectiveness of vaccines in preventing SARS-CoV-2 infection.

Test-negative case–control study using conditional logistic regression.

U.S. Department of Veterans Affairs health care system.

All veterans who had testing for SARS-CoV-2 infection between 15 December 2020 and 4 March 2021 and no confirmed infection before 15 December 2020.

SARS-CoV-2 vaccination with either the BNT-162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) vaccine as part of routine clinical care.

Effectiveness of vaccination against confirmed SARS-CoV-2 infection.

Among 54 360 persons who tested positive and 54 360 propensity score–matched control participants, the median age was 61 years, 83.6% were male, and 62% were White. Median body mass index was 31 kg/m² among those who tested positive and 30 kg/m² among those who tested negative. Among those who tested positive, 9800 (18.0%) had been vaccinated; among those who tested negative, 17 825 (32.8%) had been vaccinated. Overall vaccine effectiveness 7 or more days after the second dose was 97.1% (95% CI, 96.6% to 97.5%). Effectiveness was 96.2% (CI, 95.5% to 96.9%) for the Pfizer–BioNTech BNT-162b2 vaccine and 98.2% (CI, 97.5% to 98.6%) for the Moderna mRNA-1273 vaccine. Effectiveness remained above 95% regardless of age group, sex, race, or presence of comorbidities.

Predominantly male population; lack of data on disease severity, mortality, and effectiveness by SARS-CoV-2 variants of concern; and short-term follow-up.

Currently used vaccines against SARS-CoV-2 infection are highly effective in preventing confirmed infection in a high-risk population in a real-world setting.

None.