ABSTRACTAims  A major question in national substance use prevention efforts is how much influence parents have on their children's substance use, answers to which could determine whether current school‐based prevention programs that address peer pressure are sufficient or whether parents need to be involved. The present study examines whether parents act as gatekeepers by testing the moderator effects of parents’ substance use on the relationships of friends’ substance use to adolescent substance use (cigarettes, alcohol and marijuana).Design  A longitudinal school‐based trial for prevention of substance use in adolescents.Setting  Indianapolis, Indiana, USA.Participants  As part of a large substance use prevention trial, entering middle school students were surveyed prospectively at baseline, 6 months and 18 months (n = 1807 from 57 schools).Measurements  A self‐reported survey was used to measure behaviors, attitudes and social influences related to adolescent substance use.Findings  Results of logistic regression analyses and multiple group structural equation modeling showed that increasing numbers of parents and friends using substances were associated with greater risk of adolescent substance use, as were more substance offers and lower levels of refusal self‐efficacy. Additionally, refusal self‐efficacy mediated the effects of baseline use and substance offers on subsequent use. However, non‐using parents had a buffering effect on friends’ influences to use substances, such that friends’ use did not affect adolescent use when parents were non‐users, and the effects of substance offers on refusal self‐efficacy were weaker.Conclusions  The findings suggest that parent substance use should be addressed in adolescent substance use prevention programs, and that continuing non‐use by parents should be reinforced.