OBJECTIVES The seasonal trivalent influenza vaccine (TIV) covers two subtypes of influenza A (A/H1N1 and A/H3N2) plus one of the two influenza B lineages circulating in humans. Co-circulation of both influenza B lineages (B/Victoria and B/Yamagata) was common in Hong Kong. We examined the difference in costs and quality-adjusted life-years (QALYs) gained by quadrivalent influenza vaccine (QIV), comparing to TIV, in age-stratified populations of Hong Kong from 2001-2010 years. METHODS TIV-unmatched influenza B infection rates with QIV versus TIV were estimated by an epidemiology model. Model parameters included percentages of influenza B lineages in circulation, influenza B-associated hospital admission, age-specific population, vaccine coverage and effectiveness. Events (outpatient care, hospitalizations and death) caused by infection of the influenza B lineage not included in TIV coverage in each year were calculated. Cost savings and QALYs gained from reduced events with QIV were estimated. Incremental cost per QALY gained (ICER) by QIV versus TIV were estimated from Hong Kong’s societal perspective. RESULTS All-age mean reduction in influenza B infection rate (per 100,000) was 25.9 (95%CI 6.7-45.1). Highest age-specific rate reduction was 451.4 (95%CI 87.7-815.1) in ≥80 years, followed by 104.8 (95%CI 27.2-182.4) in 65-79 years and 13.2 (95%CI 7.0-19.4) in 6 months-4 years. Highest cost savings and QALY gain occurred in years with high percentage (81.8%-96.4%) of circulated influenza B lineage not covered by TIV. QIV was more cost-effective than TIV in 6 years when it cost USD1 more than TIV. When QIV was USD2, USD5 and USD10 more costly, it became cost-effective in 3, 3 and zero years, respectively. CONCLUSIONS QIV was cost-effective in very young and older populations. Cost-effectiveness of QIV was subjected to unit cost of QIV versus TIV and percentage of circulating influenza B lineages.