OBJECTIVES: Seniors are particularly vulnerable to complications resulting from influenza infection. Numerous influenza vaccines are available to immunize US seniors, and practitioners must decide which product to use. Options include trivalent and quadrivalent standard-dose inactivated influenza vaccines (IIV3 and IIV4 respectively), as well as a high-dose IIV3 (HD). Our research examines the public health impact, budget impact, and cost-utility of HD versus IIV3 and IIV4 for immunization of US seniors 65 years of age and older. METHODS: Our model was based on US influenza-related health outcome data. Health care costs and vaccine prices were obtained from the Centers for Medicare and Medicaid Services. Efficacies of IIV3 and IIV4 were estimated from various meta-analyses of IIV3 efficacy. The results of a head-to-head randomized controlled trial of HD vs. IIV3 were used to estimate relative efficacy of HD. Conservatively, herd protection was not considered. RESULTS: Compared to IIV3, HD would avert 195,958 cases of influenza, 22,567 influenza-related hospitalizations, and 5423 influenza-related deaths among US seniors. HD generates 29,023 more Quality Adjusted Life Years (QALYs) and a net societal budget impact of $154 million. The Incremental Cost Effectiveness Ratio (ICER) for this comparison is $5299/QALY. 71% of the probabilistic sensitivity analysis (PSA) simulations were <$100,000/QALY. Compared to IIV4, HD would avert 169,257 cases of influenza, 21,222 hospitalizations and 5212 deaths. HD generates 27,718 more QALYs and a net societal budget impact of -$17 million and as such dominates IIV4. For this comparison, 81% of PSA simulations were <$100,000/QALY. CONCLUSIONS: HD is expected to achieve significant reductions in influenza-related morbidity and mortality. Further, HD is a cost effective alternative to both IIV3 and IIV4 in seniors. Our conclusions were robust in the face of sensitivity analyses.