The Iowa Strengthening Families Program (ISFP) condition adolescents demonstrated a lower rate of increase across time on internalizing symptoms than control condition adolescents. However, ISFP did not have a significant effect on overall levels of internalizing across the time frame studied. Regarding monthly polysubstance use, ISFP adolescents demonstrated a lower overall level and a lower rate of increase across time compared with control condition adolescents. ISFP effects on the rate of increase over time for polysubstance use were stronger for girls than for boys. Overall, this study has shown that the ISFP, a universal intervention targeting youth substance use, also had positive effects on internalizing symptoms in the sample of rural midwestern adolescents. Because both adolescent internalizing symptoms and polysubstance use are serious problems that can lead to short- and long-term consequences, public health goals emphasize their prevention. This study evaluated the effects of the ISFP, a theory-based family-focused adolescent substance use preventive intervention. The study examined the longitudinal effects of ISFP on internalizing symptoms, such as depression and anxiety and monthly polysubstance use (alcohol, tobacco, marijuana, inhalants, and other illicit drugs). Appendix and references