Background: The SARS-CoV-2 vaccination campaign began on 27 December 2020 in Europe, primarily involving health workers. This study aimed to assess the SARS-CoV-2 vaccination effectiveness, as assessed by reductions in incidence, symptom severity, and further infection spreading. Methods: A retrospective cohort study was conducted on 9811 health workers operating at the Verona University Hospital, Italy, from 27 December 2020 to 3 May 2021. All health workers were offered vaccination with Comirnaty (BNT162b2, BioNTech/Pfizer, Mainz, Germany/New York, United States), and a health surveillance program was implemented with periodical swab testing. Vaccination status and clinical data were collected using an ad hoc semi-structured questionnaire and health surveillance charts. Results: As of 3rd of May, 82.5% of health workers had been vaccinated against SAR-CoV-2, and 177 (1.8%) had tested positive for SARS-CoV-2. Vaccination more than halved the cumulative incidence of SARS-CoV-2 infection and reduced by two-thirds the cumulative incidence of symptomatic subjects. In detail, most unvaccinated HWs were symptomatic; 50% reported fever, 45% reported ageusia/anosmia, and nearly 20% reported dyspnea. These percentages were much lower in HWs who had been vaccinated for at least 14 days (18% for fever and anosmia, 6% for dyspnea and ageusia). Moreover, cases of vaccine breakthrough were sixfold less likely to further spread the infection than unvaccinated HWs. Conclusions: SARS-CoV-2 vaccination reduced the infection frequency among HWs, further spreading of the infection, and the presence, severity, and duration of COVID-19-related symptoms.