Objective: To 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. Method: These 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. Results: Among 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. Conclusions: These risk factors could help clinicians identity those at risk for significant problems due to prescription misuse, allowing for prevention or early treatment in this population.