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Aims: The contribution of SARS-CoV-2 infection on lung damage and the effect of vaccination on either containing the number of deaths or mitigating lung damage has not been systematically investigated., Methods: Post-mortem analysis was performed among consecutive in-patients with COVID-19 deceased in the Province of Trieste (2020-2022). The outcomes of the study were (i) rates of in-hospital mortality, (ii) contribution of COVID-19 to death, (iii) histological extent of lung injury and (iv) impact of vaccination., Results: A total of 1038 consecutive hospitalized patients who died with SARS-CoV-2 infection were autopsied and deep histological analysis of the lungs was performed in a randomly selected sample of 508 cases. Among them, SARS-CoV-2 infection was (a) the cause of death (n = 90), (b) contributing to death (n = 304) and (c) an accompanying feature (n = 114). The incidence of SARS-CoV-2 infection as the primary cause of mortality decreased over time (23.8% in 2020, 20.9% in 2021 and 7.9% in 2022). On multivariable analysis, vaccination (any dose) was independently associated with lower rates of death related to SARS-CoV-2 infection (HR .15, p < .001), after adjusting for other independent predictors. A total of 172 patients were vaccinated at least with two doses at the time of death: 93% triple-vaccinated, 7% double-vaccinated. On histological analysis, vaccinated patients had a greater frequency of pneumonia severity score 0 and 1 (20.3% vs. 5.4% and 20.9% vs. 7.7%, p < .001, respectively), and a substantially lower proportion of pneumonia severity score 3 (26.2% vs. 55.1%, p < .001) compared to unvaccinated patients., Conclusions: COVID-19 vaccination has substantially reduced rates of death related to SARS-CoV-2 infection over time and may have the ability to mitigate lung damage., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)