The study found that the risk factors were more significantly associated with substance use than were the protective factors. Findings indicated significant risk interactions for alcohol and marijuana use and for problems with drugs and alcohol. Generally, risk factors included personal dysregulation, poor family interactions, deviant peers, and the exposure to violence in the community. Protective factors were personal belief in God followed by parent religiosity and student-teacher communication. The findings suggest that substance use among Central American adolescents is a significant problem and that interventions must address risk and protective factors from across multiple domains of an adolescent’s life. Future research should focus on the development of appropriate intervention programs for Central American youth with substance abuse and other problems. Participants were 17,215 students from Panama, Costa Rica, and Guatemala who answered a self-report survey administered during 2000-2001. The survey measured alcohol, tobacco, and other drug use; substance use problems; gang involvement; engagement in violence; depression; dysregulation; family problems with drugs and alcohol; religiosity; negative and positive family interactions and communication; school disengagement; student-teacher interaction; support from adults; peer deviance; and exposure to community violence. Data were analyzed using logistic regression models and hierarchical linear regressions. Tables, figure, references