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Adverse Childhood Experiences (ACEs) are well-documented as significant predictors of substance use in adolescence. In contrast, Positive Childhood Experiences (PCEs) have been suggested to mitigate some of the deleterious effects of ACEs. However, the interplay between ACEs and PCEs in relation to substance use has received limited empirical attention. Using data from the 2024 Florida Youth and Substance Abuse Survey (N = 18,962), this study examines the differential impact of ACEs and PCEs on substance use among Florida high school students. Our findings indicate that while ACEs exacerbate the risk of substance use, PCEs appear to confer a protective effect. Interestingly, the relationship between ACEs and substance use was more pronounced among individuals with higher exposure to PCEs. This paradoxical finding suggests that youth who experience both elevated ACEs and PCEs may be navigating conflicting psychosocial signals, with stress and trauma within the home environment juxtaposed against positive and supportive school and community relationships. As adolescents attempt to reconcile these divergent experiences, they may resort to substance use as a coping mechanism to alleviate the psychological strain induced by such internal conflict.