OBJECTIVE: To describe the design and present the baseline findings of the evaluation study of 'Paesaggi di Prevenzione', a school-based prevention program tackling smoking, alcohol misuse, dietary risks, and physical inactivity in 12- to 14-year-olds. METHODS: The program was implemented from January 2011 to April 2012 in Emilia-Romagna, Italy, and comprised classroom activities and school-wide policies. A two-arm cluster randomized controlled trial was designed. Schools were the units of randomization and were matched by socioeconomic status, size, and type. RESULTS: Data from 4700 middle school students and 2952 high school students were collected anonymously from October to December 2010. Past-30-day smoking prevalence was 1.9% among middle school students and 20.8% among high school students. Past-30-day prevalence of alcohol intoxication was 2.2% among middle school students and 11.4% among high school students. A total of 39.7% of middle school students and 48.0% of high school students drank sugar-sweetened beverages four or more times per week; 7.5% of middle school students and 7.1% of high school students had intense physical activity every day. CONCLUSIONS: This study seems adequately powered and baseline variables appear evenly distributed between study groups. Findings are in line with those of the WHO Health Behaviour in School-Aged Children study.