OBJECTIVES: Adults ≥65 years account for most seasonal influenza-related hospitalizations and deaths. A recent 32,000-participant, head-to-head RCT (FIM12, NCT01427309) demonstrated that a high-dose influenza vaccine (HD) was 24.2% more efficacious than a standard-dose influenza vaccine (SD) in adults ≥65 years. A cost-utility analysis (CUA) of HD vs. SD in FIM12 participants was performed. METHODS: Health-care resource utilization data collected in the FIM12 study included: medications, non-routine medical and emergency room visits, and hospitalizations. Utilized resources were summarized across vaccine arms and unit costs were applied, using standard US cost sources, to each resource item (including vaccines; HD $31.82; SD $12.04) to estimate the mean total direct medical and societal costs associated with each vaccine. Adverse event data from the trial were mapped to quality of life data from the literature to estimate the effectiveness of both vaccines. The time horizon was one year’s influenza season for costs and a lifetime for quality-adjusted life years (QALYs). RESULTS: The average per-participant direct medical costs (including influenza vaccine cost) and societal costs were $116 and $128 lower in the HD arm. Hospitalizations represented over 95% of the total cost and were less frequent in the HD arm (7.7% of HD participants reported ≥1 hospitalization versus 8.4% in SD arm) and average length of stay (LOS) across all participants was shorter in the HD arm (0.49 days vs 0.56 days). HD was associated with 0.0004 more QALYs per participant and, due to cost savings, dominated SD in the CUA. CONCLUSIONS: Despite the higher price of HD vs. SD, the total direct medical and societal costs were over $100 lower per vaccinee in those who received HD. This was driven by a reduction in the number of hospitalizations and in the LOS for those hospitalized. HD dominated SD in the CUA.