On March 29, 2021, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr)Messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines have been shown to be effective in preventing symptomatic COVID-19 in randomized placebo-controlled Phase III trials (1,2); however, the benefits of these vaccines for preventing asymptomatic and symptomatic SARS-CoV-2 (the virus that causes COVID-19) infection, particularly when administered in real-world conditions, is less well understood. Using prospective cohorts of health care personnel, first responders, and other essential and frontline workers* in eight U.S. locations during December 14, 2020-March 13, 2021, CDC routinely tested for SARS-CoV-2 infections every week regardless of symptom status and at the onset of symptoms consistent with COVID-19-associated illness. Among 3,950 participants with no previous laboratory documentation of SARS-CoV-2 infection, 2,479 (62.8%) received both recommended mRNA doses and 477 (12.1%) received only one dose of mRNA vaccine. † Among unvaccinated participants, 1.38 SARS-CoV-2 infections were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) per 1,000 person-days. § In contrast, among fully immunized (≥14 days after second dose) persons, 0.04 infections per 1,000 person-days were reported, and among partially immunized (≥14 days after first dose and * Occupational categories: primary health care personnel (physicians, physician assistants, nurse practitioners, and dentists), other allied health care personnel (nurses, therapists, technicians, medical assistants, orderlies, and all other persons providing clinical support in inpatient or outpatient settings), first responders (firefighters, law enforcement, corrections, and emergency medical technicians), other essential and frontline workers (workers in hospitality, delivery, and retail; teachers; and all other occupations that require contact within 3 feet of the public, customers, or coworkers as a routine part of their job). † An additional five participants received the Janssen COVID-19 vaccine (Johnson & Johnson), resulting in 2,961 vaccinated participants. § Person-days is an estimate of the time-at-risk (to SARS-CoV-2 infection) that each participant contributed to the study.