evidence: Understanding the impact of these factors, namely the emergence of variants and waning immunity, in relation to the success of vaccination programmes is of paramount importance. Post authorization analyses meet the urgent need to evaluate the magnitude and sources of changes in the effectiveness of COVID-19 vaccines implemented through different vaccination strategies and across diverse populations with a wide range of coexisting conditions. Ultimately with the aim to develop vaccine recommendations and inform public health policy. In this study, we assessed the effectiveness of the COVID-19 vaccination programme implemented in the Apulia region of Italy in preventing SARS-CoV-2 infections, COVID-19-related hospital admissions and deaths. It has been almost two years since mass vaccination campaigns using newly approved vaccines against SARS-CoV-2 started in the Apulia region. The availability of vaccination data from nearly four million people over almost two years of vaccination programme allows a comprehensive narrative about its effects on COVID-19 related outcomes. [...] Adjusted vaccine effectiveness (estimates of COX models) of the vaccination programme against COVID-19 (a) infection, (b) hospitalisation, (c) death*, by age group and time since full vaccination. Apulia region, Italy, Jan 1–Dec, 2021. *Missing estimates due to limited follow-up time and/or events. [...] Adjusted vaccine effectiveness (estimates of COX models) of the vaccination programme against COVID-19 (a) infection, (b) hospitalisation, (c) death, by vaccination status and variant. Apulia region, Italy, Jan 1–Dec, 2021.