This retrospective cohort study compared the rates of virologically-confirmed SARS-CoV-2 infections, symptomatic or lethal COVID-19 among the residents of the Italian province of Pescara who received one or two doses of COVID-19 vaccines, versus the unvaccinated. The official data of the National Health System were used, and a total of 69,539 vaccinated adults were compared with 175,687 unvaccinated. Among the subjects who received at least one vaccine dose, 85 infections (0.12%), 18 severe and 3 lethal COVID-19 cases were recorded after an average follow-up of 38 days. Among the unvaccinated, the numbers were 6948 (4.00%), 933 (0.53%) and 241 (0.14%), respectively. The serious adverse event reports-yet unconfirmed-were 24 out of 102,394 administered doses. In a Cox model, adjusting for age, gender, and selected comorbidities, the effectiveness of either BNT162b2, ChAdOx1 nCoV-19 or mRNA-1273 vaccines was higher than 95% in preventing infections (mostly due to B.1.1.7 variant), symptomatic or lethal COVID-19. No differences were observed across genders, and among the 691 subjects who received the second dose of vaccine later than the recommended date. Although preliminary, these findings support current immunization policies and may help reducing vaccine hesitancy.