Objectives To determine the past-year medical misuse prevalence for 4 controlled medication classes (pain, stimulant, sleeping, and antianxiety) among adolescents, and to assess substance use outcomes among adolescents who report medical misuse. Design A Web-based survey was self-administered by 2744 secondary school students in 2009-2010. Setting Two southeastern Michigan school districts. Participants The sample had a mean age of 14.8 years and was 51.1% female. The racial/ethnic distribution was 65.0% white, 29.5% African American, 3.7% Asian, 1.3% Hispanic, and 0.5% other. Main Outcome Measures Past-year medical use and misuse of 4 controlled medication classes. Results Eighteen percent of the sample reported past-year medical use of at least 1 prescribed controlled medication. Among past-year medical users, 22.0% reported misuse of their controlled medications, including taking too much, intentionally getting high, or using to increase alcohol or other drug effects. Medical misusers were more likely than nonmisusers to divert their controlled medications and to abuse other substances. The odds of a positive screening result for drug abuse were substantially higher among medical misusers (adjusted odds ratio, 7.8; 95% confidence interval, 4.3-14.2) compared with medical users who used their controlled medications appropriately. The odds of drug abuse did not differ between medical users who used their controlled medications appropriately and nonusers. Conclusions Most adolescents who used controlled medications took their medications appropriately. Substance use and diversion of controlled medications were more prevalent among adolescents who misused their controlled medications. Careful therapeutic monitoring could reduce medical misuse and diversion of controlled medications among adolescents.