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This study was conducted to determine the protective effect of influenza vaccine against primary major adverse cardiovascular events (MACEs) in elderly patients, especially those with influenza-like illness (ILI).This retrospective, population-based case-control study of an elderly population (age ≥ 65 years) was conducted using Taiwan's National Health Insurance Research Database (2000-2013). One control was selected for each MACE case (n = 80,363 each), matched according to age, year of study entry, and predisposing factors for MACEs. ILI and MACEs (myocardial infarction [MI] and ischemic stroke) were defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Odds ratios (ORs) were calculated for the association between MACEs and vaccination.Influenza vaccination received in the previous year was associated with reduced risks of primary MACEs overall (adjusted OR [aOR] 0.80, 95% CI 0.78-0.82, P < .001), MI (aOR 0.80, 95% CI 0.76-0.84, P < .001), and ischemic stroke (aOR 0.80, 95% CI 0.77-0.82, P < .001). ILI diagnosed in the previous year was associated with increased risks of MACEs (aOR 1.24, 95% CI 1.18-1.29, P < .001), MI (aOR 1.46, 95% CI 1.34-1.59, P < .001), and ischemic stroke (aOR 1.16, 95% CI 1.10-1.22, P < .001). Vaccination attenuated the heightened risks associated with ILI (MACEs: aOR 0.99, 95% CI 0.92-1.07, P = .834; MI: aOR 1.05, 95% CI 0.92-1.21, P = .440; ischemic stroke: aOR 0.96, 95% CI 0.89-1.05, P = .398).Results of this study suggest that influenza vaccination is associated with reduced primary MACE risks in the elderly population, including those with ILI.