Abstract Background The effectiveness of a cannabis prevention program in high school students was assessed. Methods A quasi-experimental study was designed to evaluate the effectiveness of an intervention implemented in an intervention group (IG) with 39 schools compared with a control group (CG) of 47 schools not exposed to the intervention. Of 224 secondary schools in Barcelona, 86 were assessed in the 2005–2006 school year through a personal questionnaire administered at baseline and 15 months after the intervention. Participants consisted of 4848 ninth graders (14–15 year-olds), 2803 assigned to the IG and 2043 to the CG, according to the type and size of the school and the socioeconomic status of the school's neighborhood. The intervention consisted of a school-based cannabis prevention program (xkpts.com), with four sessions and 16 activities, implemented over 6–10 h, with materials for parents and web-based student involvement. Last-month cannabis use was assessed at baseline and at 15 months’ follow-up. Process evaluation indicators were assessed. Results At 15 months follow-up, 8.2% of boys and 8.3% of girls in the IG became last-month cannabis users versus 11.8% of boys and 11.6% of girls in the CG. These differences were statistically significant ( p = 0.003), representing a 29% reduction in last-month cannabis users in the IG compared with the CG. The incidence of last-month cannabis use was lowest in classrooms that adhered to the program protocol. Conclusions The xkpts.com program was effective in preventing progression to last-month cannabis use. Effectiveness was higher in classrooms that adhered closely to the protocol.