The comorbidity of conduct and depressive problems and substance use outcomes were examined in a community-based sample of 340 African American males and females. Alcohol, tobacco, and marijuana use were examined at Grades 6, 8, and 10 based on the following group membership at sixth grade: (a) comorbid conduct and depressive problems; (b) conduct problems only; (c) depressive problems only; (d) neither conduct nor depressive problems. Overall, the two conduct problem groups displayed the highest levels of substance use, although at some time points, comorbid youth displayed significant higher substance use levels. Subjects with depressive problems only displayed levels of substance use that were equivalent to subjects in the nonproblem group. Results highlight the importance of controlling for comorbid symptoms, possible interactive effects between conduct and depressive problems, and implications for treatment and prevention of substance use.