In the early 2000s, a European team of practitioners and researchers developed the Unplugged program, designed to prevent substance use among middle school students aged 12 to 14. It was evaluated between 2004 and 2007 as part of a study conducted in seven European countries (Italy, Belgium, Austria, Sweden, Spain, Greece, and Germany). The Unplugged program was implemented in the Loiret department starting in the 2013–2014 school year at the initiative of the Association for Counseling and Support in Addiction and Substance Abuse (Apléat). During the 2016-2017 school year, Santé publique France evaluated the effectiveness of the program implemented by Apléat among 1,091 middle school students in the Loiret (grades 6 through 8). The study’s results showed that the Unplugged program reduced students’ recent use of psychoactive substances (PAS: tobacco, alcohol, cannabis) and reduced experimentation with PAS among students who, at the start of the study, had never engaged in such behaviors. The report presents a cost-benefit analysis of the Unplugged program in the French context, based on the results of this effectiveness study. The baseline analysis adopts a societal perspective incorporating a monetary valuation of years of life lost, a discount rate of 2.5% (then 1.5% after 30 years), and a “lifetime” time horizon. The following costs were included in the model: 1) costs of the Unplugged program, based on data from the initial pilot in the Loiret and from the subsequent national rollout; 2) healthcare system costs due to morbidity or mortality when these costs are caused by SPA (hospitalizations for tobacco-related cardiovascular diseases, hospitalizations for alcohol- or tobacco-related cancers, end-of-life care due to alcohol or tobacco, and smoking cessation treatments); 3) costs of years of life lost due to deaths attributable to tobacco use, alcohol use (excluding traffic accidents), or traffic accidents caused by alcohol or cannabis use. In addition to the baseline analysis, six scenarios were modeled: 1) a perspective limited to the healthcare system; 2) program costs under a less-than-optimal implementation of Unplugged; 3) a 50-year time horizon; 4) a 5-year time horizon; 5) an alternative valuation of lives lost in a traffic accident due to cannabis use; 6) no treatment effect of Unplugged 15 months after the end of the intervention. A deterministic sensitivity analysis was also conducted. The cost-benefit analysis of Unplugged estimated that 1 euro spent on the program would yield a return on investment of 6 euros when viewed solely from the perspective of the healthcare system. From a societal perspective (including the valuation of years of life lost), 1 euro spent on the program would generate 150 euros in avoided costs, all else being equal.