Conduct problems are strong positive predictors of substance use and problem substance use among teens, whereas predictive associations of depressed mood with these outcomes are mixed. Conduct problems and depressed mood often co-occur, and such co-occurrence may heighten risk for negative outcomes. Thus, this study examined the interaction of conduct problems and depressed mood at age 11 in relation to substance use and problem use at age 18, and possible mediation through peer substance use at age 16. Analyses of multirater longitudinal data collected from 429 rural youths (222 girls) and their families were conducted using a methodology for testing latent variable interactions. The link between the conduct problems x depressed mood interaction and adolescent substance use was negative and statistically significant. Unexpectedly, positive associations of conduct problems with substance use were stronger at lower levels of depressed mood. A significant negative interaction in relation to peer substance use also was observed, and the estimated indirect effect of the interaction on adolescent use through peer use as a mediator was statistically significant. Findings illustrate the complexity of multiproblem youth.