To (1) estimate the proportion of nonmedical users of prescription opioids (i.e., used prescription opioids in the past year without a doctor's orders) who used leftover medications from their own previous prescriptions; (2) assess substance use behaviors as a function of diversion source; and (3) identify the sources for these prescribed opioids. We analyzed data collected via self-administered questionnaires from nationally representative samples of high school seniors (modal age, 18 years) as a part of the Monitoring the Future (MTF) study. The sample consisted of four cohorts (senior years of 2007–2010, n = 8,888), including 647 high school seniors who reported past-year nonmedical use of prescription opioids, of whom 53% were estimated to be women. An estimated 36.9% of past-year nonmedical users of prescription opioids obtained these opioid medications from their own previous prescriptions. Logistic regression analyses indicated that nonmedical users who used leftover medications from their previous prescriptions were primarily motivated to relieve physical pain, whereas nonmedical users who obtained medications from other sources had significantly higher odds of prescription opioid abuse and other substance use behaviors. Based on a subanalysis of nonmedical users who obtained prescription opioids from their previous prescriptions in 2010 (n = 51), approximately 27.1% obtained them from a dentist, 45.0% obtained them from an emergency room physician, and 38.3% obtained them from another physician. Leftover prescription opioids from previous prescriptions represent a major source of nonmedical use of prescription opioids among high school seniors. These findings indicate that enhanced vigilance is needed when prescribing and monitoring prescription opioids among adolescents, to reduce leftover medications and nonmedical use.