In this study, the effectiveness of a life skills program to impede tobacco use in early adolescence was scrutinized. The focus was on the mediating role of yielding to peer pressure. The universal school-based life skills program IPSY (Information + Psychosocial Competence = Protection) against adolescent substance use was implemented over 3 years. Over the same time period, it was evaluated based on a longitudinal quasi-experimental design with an intervention and comparison group (4 measurement points; N = 1,657 German students, age 10 at T1). By applying a growth curve modeling approach, we found that participation in IPSY compared with non-participation predicted a slower increase in tobacco use over time, suggesting a significant intervention effect. Moreover, a parallel growth curve model revealed that less yielding to peer pressure induced by IPSY mediated the program effects on tobacco use over time.