AbstractObjectives To examine the lifetime prevalence of medical and nonmedical use of prescription benzodiazepine anxiolytics among U.S. high school seniors and to assess substance use behaviors based on lifetime histories of medical and nonmedical use of prescription benzodiazepine anxiolytics. Methods Nationally representative samples of high school seniors were surveyed during their senior year via self-administered questionnaires. The sample consisted of 11,248 high school seniors (modal age, 18 years) from five independent cohorts (2007–2011). The sample was 52% female, 65% White, 12% African American, 15% Hispanic, and 7% other. Results The lifetime prevalence of medical use of prescription benzodiazepine anxiolytics was 4.9%, while the lifetime prevalence of nonmedical use was 7.5%. Although lifetime prevalence rates were relatively stable over time, there were notable sex and racial/ethnic differences in medical and nonmedical use behaviors. Among those who were ever prescribed benzodiazepine anxiolytics (n = 530), approximately 40.6% reported medical use only, 27.4% reported medical use prior to nonmedical use, and 32.0% reported nonmedical use prior to medical use. The odds of substance use behaviors were greater among those who reported any history of nonmedical use relative to non-users, while the odds of substance use behaviors did not differ between medical users only and non-users. Conclusions One in every ten U.S. high school seniors has ever had some exposure to prescription benzodiazepine anxiolytics either medically or nonmedically. Benzodiazepine anxiolytics prescribed to adolescents should be closely monitored, safely stored, and properly disposed to reduce nonmedical use due to leftover medication and peer diversion.