BACKGROUND: Given the increase in overweight and obesity prevalence in adolescents in the last decade, effective prevention strategies for these conditions in adolescents are urgently needed. The PRALIMAP (Promotion de l'ALImentation et de l'Activité Physique) trial aims to evaluate the effectiveness for these conditions of 3 health promotion strategies--educational, screening and environmental--applied singly or in combination in high schools over a 2-year intervention period. METHODS: PRALIMAP is a stratified 2 × 2 × 2 factorial cluster randomised controlled trial including 24 state high schools in Lorraine, northeastern France, in 2 waves: 8 schools in 2006 (wave 1) and 16 in 2007 (wave 2). Students entering the selected high schools in the 4 academic years from 2006 to 2009 are eligible for data collection. Interventional strategies are organized over 2 academic years. The follow-up consists of 3 visits: at the entry of grade 10 (T0), grade 11 (T1) and grade 12 (T2). At T0, 5,458 (85.7%) adolescents participated. The educational strategy consists of nutritional lessons, working groups and a final party. The screening strategy consists in detecting overweight/obesity and eating disorders in adolescents and proposing, if necessary, an adapted care management program of 7 group educational sessions. The environmental strategy consists in improving dietary and physical activity offerings in high schools and facilities, especially catering. The main outcomes are body size evolution over time, nutritional behaviour and knowledge, health and quality of life. An evaluation process documents how each intervention strategy is implemented in the schools and estimates the dose of the intervention, allowing for a per protocol analysis after the main intention-to-treat analysis. DISCUSSION: PRALIMAP aims at improving the prevention and management of overweight and obesity in adolescents by translating current evidence into public health practice. Particular attention is paid to clustering, multiple factorials and long-term duration to address common pitfalls in health promotion trials. The results should inform how best to implement, in a school environment, effective nutrition prevention programs targeting adolescents who are at a point their lives when they develop responsibilities and empowerment for health attitude behaviours. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov under NCT00814554.