OBJECTIVES: Current influenza vaccination practice using trivalent inactivated vaccine (TIV) and trivalent live attenuated influenza vaccine (LAIV) covers only one of two commonly circulating influenza B lineages; mismatch and co-circulation are frequent and unpredictable.  We evaluated the health outcomes and cost-effectiveness of universal vaccination with QIV compared with current vaccination practice. METHODS: We used a 1-year decision-tree from a societal perspective, including influenza-associated productivity losses and death. US Population was stratified to model age-specific (<5, 5-17, 18-49, 50-64, and 65+) vaccination coverage, vaccine efficacy and risks of influenza complications. Rates of influenza, healthcare utilization, disease-related costs, and survival were estimated from published data where possible.  Annual cases, lifetime costs (2011 USD) and quality adjusted life years (QALYs) lost were calculated and discounted (3% per annum) appropriately. We conducted one-way and probabilistic sensitivity analyses. RESULTS: Results suggest that vaccination with QIV instead of TIV/LAIV is expected to yield 77,817 fewer medically-attended influenza cases, approximately 4,360 fewer related hospitalizations and 868 fewer deaths per year. QIV vaccination is expected to result in approximately 4,342 fewer QALYs lost compared with TIV/LAIV. The model projects QIV to be cost-effective at $50,000/QALY, excluding death-related productivity losses, avoiding double counting as death-related QALYs are included, at a price increment of 35% over the average weighted TIV price. The increase in vaccination costs ($385 million) is offset by a $411 million reduction in influenza-related treatment costs, comprising $142 million in direct medical costs (physician visits, antivirals, and outpatient and inpatient care) and $269 million in direct non-medical cost savings.  Results were robust in sensitivity analyses.  CONCLUSIONS: Under the model assumptions, a strategy of vaccination with a quadrivalent influenza vaccine is expected to be a cost-effective alternative to current practice, by reducing the costs as well as cases, hospitalizations and deaths associated with vaccine-mismatched influenza B disease.