The aim of this study was to investigate factors mediating the effects of Luoghi di Prevenzione (LdP) smoking prevention intervention based on social competence and social influence approaches, and characterized by peer-led school-based interventions, out-of-school workshops, school lessons, and by enforcing the school anti-smoking policy. Students aged 14-15 years in 13 secondary schools in Reggio Emilia, Italy (989 students) were randomly assigned to the LdP intervention or a control condition. The baseline and follow-up surveys were carried out before and 18 months after the intervention, respectively. The outcomes were cigarette daily and frequent smoking and smoking at school. Multilevel multiple mediation analyses were carried out in order to study effect mediation. The mediators were normative perception, positive and negative beliefs, refusal skills for smoking, social acceptability perception, risk perception, smoking knowledge and awareness about dangers of second-hand smoking. The intervention effects were explained by the social influence component through the mediator refusal skills for smoking. The programme also showed to significantly increase risk perception and smoking knowledge, even though these mediators had no effect on smoking. Moreover, LdP intervention directly reduced smoking in school areas. Future interventions should maintain and strengthen the LdP social influence component and the part regarding the school anti-smoking policy.