Objectives. To present data for opioid misuse among US reservation-based American Indian (AI) adolescents and to compare these data with national rates from Monitoring the Future (MTF).Methods. Data were from a national sample of 33 schools participating in a substance use epidemiological survey of reservation-based AI adolescents during 2018 and 2019. Participants were 8th-, 10th-, and 12th-grade AI students (n = 1592). Measures included 12-month and 30-day use of OxyContin, Vicodin, heroin, and narcotics. We computed prevalence and compared it with MTF national prevalence.Results. Across grades, AI youths demonstrated significantly greater past 12-month and 30-day opioid use relative to a national sample. Significant absolute differences in 12-month and 30-day prevalence levels ranged from 1.6% (8th-grade heroin) to 4.7% (12th-grade narcotics) and from 1.6% (12th-grade narcotics) to 1.8% (12th-grade heroin), respectively.Conclusions. Opioid misuse prevalence levels were significantly greater for reservation-based AI adolescents relative to national prevalence levels.Public Health Implications. Findings suggest that implementation of evidence-based efforts, adapted or developed to be culturally appropriate, should be significantly increased in tribal communities, along with policies to address the unique social, economic, and health issues they face.