"Eigenständig werden 5+6" (Becoming independent 5+6) is a German school-based smoking prevention program that draws on social competence and social influence approaches. It was investigated whether the program’s effect on smoking onset is mediated by substance-specific skills and cognitions such as knowledge, attitudes/risk perception, normative expectations, resistance skills, and refusal self-efficacy. Multiple mediation analyses revealed a statistically significant total indirect effect that accounted for 30.8% of the total effect. When considered separately, significant indirect effects could be found for normative expectations concerning peer smoking and the resistance skill of saying ‘no’. Between these two mediators, the percentage of total effect mediated varied between 9.8% and 10.3%. Results of the current study emphasize the importance of substance-specific skills and cognitions in the effectiveness of school-based programs combining social competence and social influence curricula in preventing adolescent smoking onset.