Age-specific force of varicella infection, hospitalisation and death rates in non-immune persons were calculated using an age-based mathematical model and national data for France. A cost-effectiveness model was then applied to hypothetical cohorts of persons aged 15-45 years with a negative or uncertain history of varicella. Vaccination strategies with and without prior serotesting, and healthcare payer perspective and societal perspective were considered. A sensitivity analysis was performed. Vaccination prevented more than one third of all varicella-related deaths. With serotesting, compared with no intervention, the cost per case avoided and per year of life saved for subjects aged 15 years were 335 and 55,100 Euro, respectively. When work-loss costs were also included, savings were associated with screening and vaccination of subjects less than 30 years old. Without serotesting, the costs raised markedly, with an almost identical effectiveness, resulting in an unfavourable incremental cost-effectiveness. Based on medical costs, routine serotesting and varicella vaccination for French adolescents and young adults with a negative or uncertain history of varicella affords health benefits at a cost comparable to those of other very expensive therapies considered worthwhile. From the societal perspective, such screening and vaccination might save costs.