OBJECTIVES: To evaluate the cost-effectiveness of the MF59 adjuvanted influenza vaccine versus non-adjuvanted vaccine in the “at risk” adult population (age 18-64) in France. A central feature of the analysis was the occurrence of antigenic drift and its effect on vaccination efficacy against influenza. Antigenic drift is a mutation in the influenza virus, so that an immune system response that combats influenza one year may not provide complete protection the following year. METHODS: A decision-analytic model was developed using evidence from clinical studies to compare relative effectiveness of MF59 adjuvanted influenza vaccine and non-adjuvanted vaccine in years when antigenic drift occurs. Data on the impact on hospitalisations, GP visits and mortality was taken from a case-control study, with other resource use parameters and costs from the literature. The analysis was performed from the payer perspective (direct medical costs) for “at risk” adults in France. “At risk” is defined as persons with comorbidities such as diabetes and respiratory problems who have elevated risk of developing complications. RESULTS: MF59 adjuvanted influenza vaccine maintains effectiveness post antigenic drift more than non-adjuvanted vaccines. It was estimated that in an average year 14% of viral strains drift. Using this estimate, for an attack rate of influenza-like illness of 6% and a 3% discount rate, the incremental cost per life year gained (ICLYG) was €19,358. In a pessimistic scenario where 100% of viral strains drift, the ICLYG was €204. ICLYG was most sensitive to hospitalisation rate, extent of antigenic drift and vaccine price. CONCLUSION: The incremental CLYG is well within acceptable European thresholds. Compared to non-adjuvanted vaccines, MF59 adjuvanted vaccine can be considered cost-effective for the “at risk” adult population aged <65 years in France and close to cost-neutral in years when antigenic drift occurs, protecting better individuals at higher risk of complications and hospitalisation.