Based on 2018 national estimates, approximately 5-10% of youth between the ages of 12-17 report past year prescription drug misuse (PDM) in the United States. PDM among adolescents is associated with negative health outcomes and risk behaviors. The current study examined both the prevalence of PDM among diverse groups of adolescents and the association of alcohol and cigarette use with early PDM.Data came from the cross-sectional state-based 2018 Indiana Youth Survey of students from grades 6-12, ranging in age from 10 to 17 years (n = 80,926). Lifetime PDM, alcohol, and cigarettes were assessed by self-report, including ages at first use. A series of analyses were conducted separately for non-Hispanic Black, non-Hispanic White, and Hispanic students. We estimated the prevalence of PDM. Likelihood of PDM was estimated using the Kaplan-Meier survivor function. Cox proportional hazards regression models estimated age at first PDM from ages at first use of alcohol and cigarettes.Three percent of non-Hispanic Black, 4% of non-Hispanic White, and 5% of Hispanic students reported PDM. Onset of smoking was associated with first PDM across adolescence for all groups. Onset of drinking was associated with first PDM among Hispanic students across adolescence. For Non-Hispanic Black and Non-Hispanic White students, likelihood of PDM was most pronounced during very early adolescence.Onset of alcohol and cigarette use were associated with of PDM among Indiana youth, suggesting that interventions aimed at preventing early smoking and drinking may also reduce PDM among youth.