This study investigated the long-term effectiveness of a Life Skills program with regard to use and proneness to legal and illicit drug use across a 4.5-year study interval. The universal school-based Life Skills program IPSY (Information + Psychosocial Competence = Protection) against adolescent substance use was implemented over 3 years (basic program in grade 5 and booster sessions in grades 6 and 7). Over the same time period, it was evaluated based on a longitudinal quasi-experimental design with intervention and control group, including two follow-up assessments after program completion [six measurement points; N (T1) = 1657 German students; M age (T1) = 10.5 years]. Applying an HLM approach, results showed that participation in IPSY had a significant effect on the frequency of smoking, and proneness to illicit drug use, across the entire study period. In addition, shorter-term effects were found for the frequency of alcohol use in that intervention effects were evident until the end of program implementation but diminished 2 years later. Thus, IPSY can be deemed an effective intervention against tobacco use and proneness to and use of illicit drugs during adolescence; however, further booster sessions may be necessary in later adolescence to enhance youths' resistance skills when alcohol use becomes highly normative among peers.