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Background. Mental health and wellbeing, including addressing impacts of historical trauma and substance use among young people, has been identified as a key priority by Indigenous communities and leaders across Canada and globally. Yet, research to understand mental health among young Indigenous people who have used drugs is limited. Aims. To examine longitudinal risk and strengths-based factors associated with psychological distress among young Indigenous people who use drugs. Method. The Cedar Project is an ongoing cohort study involving young Indigenous people who use drugs in Vancouver, Prince George, and Chase, British Columbia, Canada. This study included participants who completed the Symptom Checklist-90-Revised, returned for follow-up between 2010 and 2012, and completed the Childhood Trauma Questionnaire. Adjusted linear mixed-effects models estimated effects of study variables on changes in area T-scores of psychological distress. Results. Of 202 eligible participants, 53% were women and the mean age was 28 years. Among men, childhood mal- treatment (emotional abuse, physical abuse, sexual abuse, physical neglect), any drug use, blackouts from drinking, and sex work were associated with increased distress. Among women, childhood maltreatment (emotional abuse, physical abuse, physical neglect), blackouts from drinking, and sexual assault were associated with increased distress, while having attempted to quit using drugs was associated with reduced distress. Marginal associations were observed between speaking their traditional language and living by traditional culture with lower distress among men. Conclusion. Culturally safe mental wellness interventions are urgently needed to address childhood trauma and harmful coping strategies that exacerbate distress among young Indigenous people who use drugs. [ABSTRACT FROM AUTHOR]