ObjectiveTo examine the risk factors associated with adolescent (ages 12–17) misuse of opioids, stimulants, tranquilizers, and sedatives using a nationally representative sample. The characteristics associated with symptoms of abuse and/or dependence related to prescription medication misuse among adolescents were also analyzed. MethodThese questions were addressed using the 2005 National Survey on Drug Use and Health. Screening and full interview response rates were 91% and 76%, respectively, and data from 18,678 adolescents were used. Regression analyses, using population-based weights, were performed to identify characteristics associated with past year misuse of prescription medications and the presence of past year abuse or dependence symptoms related to misuse. ResultsAmong adolescents, 8.2% misused a medication and 3.0% endorsed symptoms of a substance use disorder related to prescription medication misuse in the past year. The predictors of misuse from multivariate analyses were poorer academic performance (odds ratio [OR] 2.9,95% confidence interval [CI] 2.37–3.52), past year major depression (OR 3.1, 95% CI 2.62–3.74), higher risk-taking levels (OR 3.6, 95% CI 3.13–4.20), past year use of alcohol (OR 7.3, 95% CI 6.19–8.59), cigarettes (OR 8.6,95% CI 7.43–9.91), marijuana (OR 9.9,95% CI 8.53–11.44), or past year use of cocaine or an inhalant (OR 10.7, 95% CI 8.98–12.72). Past year major depression (OR 1.5, 95% CI 1.03–2.25), past year cocaine or inhalant use (OR 1.7, 95% CI 1.21–2.41), or≥10 episodes of past year prescription misuse (OR 3.0, 95% CI 2.13–4.17) was associated with having symptoms of abuse of or dependence among adolescent prescription medication misusers. ConclusionsThese risk factors could help clinicians identify those at risk for significant problems due to prescription misuse, allowing for prevention or early treatment in this population. J. Am. Acad. Child Adolesc. Psychiatry, 2008; 47 (7): 745–754.