OBJECTIVES: Influenza burden might be reduced by replacing current trivalent influenza vaccines (TIV, containing one B lineage) with quadrivalent vaccines (QIV, containing both Yamagata and Victoria influenza B lineages). This study (ClinicalTrials.gov: NCT01599390) assessed the potential added benefit of QIV versus TIV use on the prevention of influenza-attributable hospitalizations and deaths in the United States during 12 influenza seasons (July 1997–April 2009) as a consequence of preventing influenza B lineage mismatch. METHODS: Hospitalization and mortality data from the Nationwide Inpatient Sample and National Vital Statistics System databases, respectively, were used to quantify the influenza-attributable burden through virus-guided regression models. Based on Reed’s probability model (Reed et al, Vaccine 2012;30:1993-8), a simple multiplier model was developed to estimate the “respiratory disease broadly defined” (RDBD) outcome rates had B lineage mismatch seasons been avoided. Hospitalizations and deaths with any mention of RDBD diagnostic codes (respiratory disease, cough, abnormalities of breathing, fever or viral infections not otherwise specified) were considered influenza-attributable. The model used available vaccine coverage data (primary source: CDC Morbidity & Mortality Weekly Reports; secondary sources: National Health Interview Survey reports, National Immunization Survey, Behavioral Risk Factor Surveillance System) and vaccine effectiveness values from the literature. RESULTS: The highest numbers of QIV-preventable hospitalizations and deaths were attributed to ≥75-year-olds: 3,141 and 461 on average per season, respectively. During the worst mismatched season (2007/2008), across all ages, 20% and 28% of influenza-attributable hospitalizations and deaths, respectively, may have been QIV-preventable. CONCLUSIONS: The seasonal variability of influenza B lineage circulation and the level of vaccine match determine the extent of the benefit of QIV use. However, on average, under reasonable assumptions of vaccine effectiveness, a substantial number of hospitalizations and deaths could have been prevented by using QIV during the study period in the United States. Funding: GlaxoSmithKline Biologicals SA