A guideline called FRAMM, which is an acronym in Swedish for the most important parts of this guideline, namely “fluoride”, “advice”, “arena”, “motivation” and “diet”, was implemented in 2008 in the Västra Götaland Region in Sweden. This guideline included fluoride varnish applications performed at school twice a year at six-monthly intervals for all 12- to 15-year-olds, together with lessons on oral health. The aim of this analysis was to estimate the long-term cost-effectiveness, using prognostic calculations, of the FRAMM Guideline for 12- to 15-year-olds, compared with routine care, until the participants were 23 years old. A cost-effectiveness analysis was performed from a health care perspective, based on four years of verified data and seven years of prognosis. Data from FRAMM were combined with cost data from price lists in Sweden. The cost-effectiveness was analyzed by relating the difference in costs to the difference in the number of approximal surfaces with fillings and/or dentin lesions (DFSa). The analysis shows that FRAMM was considered dominant compared to the controls in all alternative scenarios, hence costs were prognosed to be lowered and outcomes were prognosed to be improved. A dental health program like the FRAMM Guideline with fluoride varnish during the caries risk period from 12 to 15 years is predicted to be cost-effective in the longer perspective. To further study the actual long-term caries increment after a preventive dental health program would be of great interest to verify these results.