BackgroundDespite declines over recent years, youth tobacco and other substance use rates remain high. Latino youth are at equal or increased risk for lifetime tobacco, alcohol, marijuana, and other illicit drug use compared with their white peers. Family plays an important and influential role in the lives of youth, and longitudinal research suggests that improving parenting skills may reduce youth substance use. However, few interventions are oriented towards immigrant Latino families, and none have been developed and evaluated using a community-based participatory research (CBPR) process that may increase the effectiveness and sustainability of such projects. Therefore, using CBPR principles, we developed a randomized clinical trial to assess the efficacy of a family-skills training intervention to prevent tobacco and other substance use intentions in Latino youth.Methods/DesignIn collaboration with seven Latino community-serving agencies, we will recruit and randomize 336 immigrant families, into intervention or delayed treatment conditions. The primary outcome is youth intention to smoke 6 months post intervention. The intervention consists of eight parent and four youth sessions targeting parenting skills and parent–youth relational factors associated with lower smoking and other substance use in youth.DiscussionWe present the study protocol for a family intervention using a CBPR randomized clinical trial to prevent smoking among Latino youth. The results of this trial will contribute to the limited information on effective and sustainable primary prevention programs for tobacco and other substance use directed at the growing US Latino communities.Trial registrationClinicalTrials.gov: NCT01442753