Communities That Care (CTC) is a universal, science-based community prevention system designed to reduce risk, enhance protection, and prevent adolescent health and behavior problems community wide. CTC has been found to have sustained effects on cigarette use and delinquent and violent behaviors in grade 10 in a panel of 4,407 students followed from fifth grade in a community randomized trial. It is important to test variation in the effects of this prevention system designed to be universal to understand for whom it is most effective and whether it fails to produce change or leads to iatrogenic effects for certain categories of individuals. The present study examined variation in the sustained effects of CTC on tenth-grade cigarette use and delinquent and violent behaviors. Interaction analyses suggest that the effect of CTC did not differ between those who had high levels of community-targeted risk factors at baseline or had already engaged in substance use, delinquency, or violence at baseline versus those who had not. Although CTC reduced the prevalence of both girls’ and boys’ problem behaviors, the effect on delinquency was marginally (p = 0.08) larger for boys than for girls.