OBJECTIVES: Benefits of QIV over trivalent inactivated vaccine (TIV) are dependent on the proportion of influenza circulation attributable to influenza-B and the extent of vaccine matching with respect to circulating B-lineages. Applying the 2000-2010 influenza data from the Health Protection Agency, the impact of vaccination with QIV versus TIV on influenza morbidity and mortality in the UK was evaluated to estimate potential benefits of QIV if it had been available during this time. METHODS: Using current influenza management guidance (vaccination of those at-risk and the elderly), a multi-cohort, static, 1-year decision model was used. Influenza A and B was accounted for separately. Vaccine efficacy data was derived from Cochrane Databases (TIV) and meta-analyses (QIV). The model considers the perspective of the UK National Health Service. RESULTS: Using the average influenza-B circulation and vaccine matching data over 2000-2010, 17,088 additional cases, 337 additional hospitalizations and 168 additional deaths could potentially be avoided annually with QIV versus TIV. There would be no additional benefits for well-matched years 2000-03 and 2009-10. In mismatched years benefits could range from minor, such as 2003-4 (100% mismatched, 0.4% influenza-B circulation) where 578 additional cases, 11 additional hospitalizations and 6 additional deaths potentially avoided to significant impact, such as 2005-6 (98.8% mismatched, 70% influenza-B circulation) with 100,296 additional cases, 1,976 additional hospitalizations and 988 additional deaths potentially avoided. CONCLUSIONS: Our analysis predicts that using recent influenza-B circulation and vaccine matching data, in 6 out of 10 years, a strategy of vaccination with QIV would have been more effective than TIV in reducing the number of influenza cases, and associated hospitalisations and deaths. Retrospective analysis of influenza circulation suggests that co-circulation of influenza-B lineages persists and that mismatch is frequent and unpredictable. The use of QIV might aid in reducing the associated burden of mismatched influenza-B.