Seasonal influenza is an important cause of morbidity and mortality, particularly among the elderly population. Determinants of vaccination uptake and its impact on health outcomes in the seasons 2014/2015-2016/2017 in elderly living in Treviso area (Veneto Region, North-Eastern Italy) were evaluated. A retrospective cohort study was conducted combining information from several health administrative databases, and multiple Poisson regression models were applied to evaluate the influenza vaccine effectiveness, also adjusting for confounding factors. MF59-adjuvanted trivalent-inactivated vaccine was mainly administered. Data from more than 83,000 elderly people were analyzed by year. Vaccine coverage was about 50%; influenza vaccination uptake was independently associated with older age, male sex, increasing number of underlying chronic conditions, previous pneumococcal vaccination, annual expenses for specialist medical cares, and general practitioner to whom the elderly was in charge. After adjusting for previously described characteristics, vaccination was associated with lower mortality and influenza-related hospitalization rates. Specifically, during influenza season the adjusted incidence rate ratio of death and of influenza-related hospitalizations for vaccinated compared to unvaccinated persons was 0.63 [95% confidence interval (CI) 0.58-0.69, p < .001] and 0.86 (95% CI 0.81-0.91, p < .001), respectively. A similar effectiveness was estimated for death in all age groups (≤74, 75-84, ≥85 years old), whereas a higher effect was found for hospitalizations in subjects aged ≥75 years old. Vaccination was also effective both in males and females. Findings suggest a health benefit of the influenza vaccination in the elderly population. Efforts should be focused on strategies to increase the vaccination uptake as important instrument of prevention.