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Background: Adolescents and young adults with risk factors for opioid misuse and opioid use disorder are at elevated risk for overdose. We examined prior non-fatal overdose experiences among at-risk adolescents/young adults to inform prevention efforts., Methods: Adolescents/young adults (ages 16-30) in two US emergency departments self-reporting past year opioid misuse or opioid use plus a misuse risk factor completed a baseline survey as part of an ongoing randomised controlled trial. We describe baseline factors associated with (a) overall non-fatal overdose experiences and (b) groups based on substance(s) used during the worst overdose experience., Results: Among 771 participants (27.9% male), 40.7% reported a non-fatal overdose experience. Compared with those without a prior overdose experience, those with prior overdose experience(s) were less likely to be heterosexual, and more likely to report a prior suicide attempt and greater peer substance misuse. Regarding the worst overdose experience, substance(s) included: 36.6% alcohol only, 28.0% alcohol and cannabis, 22.6% alcohol with other substance(s) and 12.7% other substance(s) only (eg, opioids). Compared with the alcohol only group, the alcohol and cannabis group were younger and less likely to be heterosexual; the alcohol with other substance(s) group were older and had greater peer substance misuse; and the other substance(s) only group were more likely to be male, receive public assistance, screen positive for anxiety and less likely to be heterosexual., Conclusions: Among at-risk adolescents/young adults, findings support the need for tailored overdose prevention efforts based on substance(s) used, with consideration of sexuality, mental health and peer substance use., Trial Registration Number: NCT04550715., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)