Evidence-based preventive interventions for adolescent substance use, violence, and mental health issues are increasingly being adapted and disseminated internationally. In the present paper, we report the results of an effectiveness study that was part of a comprehensive initiative by a coalition of health promotion organizations in the Lombardy region of Italy to select, culturally adapt, implement, evaluate, and sustain an evidence-based drug abuse prevention program developed in the USA. Findings are presented from a large-scale effectiveness study of the Life Skills Training prevention program among over 3000 students attending 55 middle schools in Italy. The prevention program taught drug refusal skills, antidrug norms, personal self-management skills, and general social skills. Relative to comparison group students, students who received the prevention program were less likely to initiate smoking at the post-test and 2-year follow-up, and less likely to initiate weekly drunkenness at the 1-year follow-up. The program had direct positive effects on several cognitive, attitudinal, and skill variables believed to play a protective role in adolescent substance use. The findings from this study show that a drug abuse prevention program originally designed for adolescents in the USA is effective in a sample of Italian youth when a rigorous and systematic approach to cultural adaptation is followed that incorporates the input of multiple stakeholders.