Substance use and related problems were assessed in a sample of primary care patients (n = 450) ages 13-21 who screened positive for depression at a clinic visit. Patients were classified as having no substance use (n = 248), non-problematic use (substance use without reported school, work, social, or family problems, n = 90), or use that reportedly caused problems in at least one area (n = 112). In logistic regression models, older age, externalizing symptoms, and not being African American were significantly associated with non-problematic use; older age, male gender, externalizing symptoms, Caucasian/White ethnicity/race, and more friends were associated with problematic use. Odds ratios were similar for patients reporting non-problematic and problematic use, suggesting that, in the presence of depression, any substance use merits evaluation and monitoring to determine treatment needs and to prevent escalation of dysfunction.