BackgroundLifetime prevalence of non-medical prescription opioid use (NMPOU) among adolescents exceeds 10%. Building on that work, we estimate lifetime and recent (i.e., past 30-day) NMPOU and examine associations with alcohol and cannabis use. MethodsWe used 2019 YRBS data from 38 states with a question on lifetime NMPOU (n = 151,910), a subsample of 8 states also inquired about recent NMPOU (n = 28,439). We estimated the prevalence and frequency of NMPOU for boys and girls in each state. Multivariable logistic regression was used to derive odds ratios (OR) and 95% confidence intervals (CIs) representing recent NMPOU in association with alcohol and cannabis use adjusting for state, race/ethnicity, and grade. ResultsThe prevalence of lifetime NMPOU ranged from 9.4% to 22.7% for girls and 8.6% to 23.2% for boys; significant sex difference in Florida. Recent NMPOU among lifetime users ranged from 33.0% to 50.7% for girls and 40.7% to 52.3% for boys, no significant sex differences. Students reporting recent NMPOU had significantly higher odds of recent alcohol (OR: 5.1, 95% CI: 4.3–6.1) and cannabis use (OR: 3.7, 95% CI: 2.8–4.8). Higher frequency (1–2 and ≥ 3 times vs. 0 times) of NMPOU had significantly greater odds of alcohol (3–9-fold) and cannabis use (3–5-fold). The magnitude of association was higher for boys compared to girls. ConclusionThe prevalence of recent NMPOU among lifetime users is high and is associated with alcohol and cannabis use. NMPOU can be a steppingstone towards other forms of opioid use therefore, opioid prevention programs should emphasize prescription drug misuse and consider socio-contextual and geographical variations.