ObjectivesThis study evaluated relative vaccine effectiveness (rVE) of MF59-adjuvanted trivalent inactivated influenza vaccine (aTIV) vs high-dose trivalent inactivated influenza vaccine (HD-TIV) for prevention of test-confirmed influenza emergency department visits and/or inpatient admissions (“ED/IP”) and for IP admissions alone pooled across the 2017–2020 influenza seasons. Exploratory individual season analyses were also performed. MethodsThis retrospective test-negative design study included United States (US) adults age ≥65 years vaccinated with aTIV or HD-TIV who presented to an ED or IP setting with acute respiratory or febrile illness during the 2017–2020 influenza seasons. Test-positive cases and test-negative controls were grouped by vaccine received. The rVE of aTIV vs HD-TIV was evaluated using a combination of inverse probability of treatment weighting and logistic regression to adjust for potential confounders. ResultsPooled analyses over the three seasons found no significant differences in the rVE of aTIV vs HD-TIV for prevention of test-confirmed influenza ED/IP (−2.5% [−19.6, 12.2]) visits and admissions or IP admissions alone (−1.6% [−22.5, 15.7]). The exploratory individual season analyses also showed no significant differences. ConclusionsEvidence from the 2017–2020 influenza seasons indicates aTIV and HD-TIV are comparable for prevention of test-confirmed influenza ED/IP visits in US adults age ≥65 years.