The purpose of this study is to assess risk factors, including other substance use, for nonmedical prescription opioid use among U.S. adolescents.A secondary data analysis of the 2017 Youth Risk Behavior Survey was conducted (n=10,175) in 2018. The outcome was nonmedical prescription opioid use. Predictor variables included other substance use, mood, sleep, academic performance, and demographic characteristics. Survey-weighted procedures in SAS, version 9.4 were used, and an adjusted logistic regression model was conducted.Among the sampled adolescents, 13.8% (95% confidence limit=12.4%, 15.3%) reported nonmedical prescription opioid use. Nonmedical prescription opioid use was more likely among participants aged 15 years (versus 16 years), American Indian/Alaskan Natives, and those who reported being sad or hopeless. All other substance use was significantly associated with increased odds of nonmedical prescription opioid use. Nonmedical prescription opioid use was 1.5 times more likely among electronic vapor users (AOR=1.58, 95% CI=1.34, 1.86), 2 times more likely among cigarette (AOR=2.49, 95% CI=2.16, 2.88) and marijuana users (AOR=2.45, 95% CI=2.05, 2.93), and almost 3 times as likely among alcohol users (AOR=2.98, 95% CI=2.18, 4.07).Study findings suggest a need for more interventions for nonmedical prescription opioid use among adolescents in the U.S. Information on nonmedical prescription opioid use should be added to all substance use prevention programs for adolescents. Moreover, future research needs to identify longitudinal predictors of adolescent nonmedical prescription opioid use to inform prevention efforts.