Four years of longitudinal data from 2,153 families with a 5th- or 6th-grade preadolescent participating in a family-focused pediatric primary-care-based prevention program were used to examine whether prevention effects were moderated by positive parenting and/or adolescent gender. Alcohol and tobacco use, internalizing problems, and externalizing problems were examined. Although findings revealed no main effect of the prevention program, positive parenting and adolescent gender were moderators of internalizing problems and adolescent gender was a moderator of externalizing problems. Clinical implications and future directions for research are discussed.