The European Smoking Prevention Framework Approach (ESFA) study in six countries tested the effects of a comprehensive smoking prevention approach after 24 (T3; N = 10,751) and 30 months (T4; N = 9,282). The programme targeted four levels, i.e. adolescents in schools, school policies, parents and the community. In Portugal, 12.4% of the T1 non-smokers in the control group had started smoking at T4 compared to 7.9% of the experimental group. Smoking onset in the experimental group was thus 36% lower. In Finland, 32.4% of the T1 non-smokers started smoking compared to 27.6% of the experimental group, implying a 15% lower onset in the experimental group. In Spain, 33.0% of the T1 non-smokers in the control group had started smoking, compared to 29.1% of the experimental group, implying a 12% lower onset. In The Netherlands, the ESFA programme was effective for non-native adolescents with 11.4% new weekly smokers compared to 19.9% in the control group. An opposite effect was found in native Dutch adolescents with 19.0% new weekly smokers in the comparison group compared to 24.0% new smokers in the experimental group. Future programmes should use more standardized ways to assess process evaluations and should assess which elements are responsible for behavioral effects.