OBJECTIVES To determine the prevalence of medical and nonmedical use of prescription opioids among high school seniors in the United States and to assess substance use behaviors based on medical and nonmedical use of prescription opioids. DESIGN Nationally representative samples of high school seniors (modal age 18 years) were surveyed during the spring of their senior year via self-administered questionnaires. SETTING Data were collected in public and private high schools. PARTICIPANTS The sample consisted of 7374 students from 3 independent cohorts (2007, 2008, and 2009). OUTCOME MEASURES Self-reports of medical and nonmedical use of prescription opioids and other substance use. RESULTS An estimated 17.6% of high school seniors reported lifetime medical use of prescription opioids, while 12.9% reported nonmedical use of prescription opioids. Sex differences in the medical and nonmedical use were minimal, while racial/ethnic differences were extensive. More than 37% of nonmedical users reported intranasal administration of prescription opioids. An estimated 80% of nonmedical users with an earlier history of medical use had obtained prescription opioids from a prescription they had previously. The odds of substance use behaviors were greater among individuals who reported any history of nonmedical use of prescription opioids relative to those who reported medical use only. CONCLUSIONS Nearly 1 in every 4 high school seniors in the United States has ever had some exposure to prescription opioids either medically or nonmedically. The quantity of prescription opioids and number of refills prescribed to adolescents should be carefully considered and closely monitored to reduce subsequent nonmedical use of leftover medication.