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BACKGROUND: Polysubstance use (PSU), defined as the use of multiple psychoactive substances, is associated with a heightened risk of subsequent health issues, including substance use disorders. However, the interplay between genetic susceptibility and environmental exposures in PSU initiation during adolescence remains understudied.METHODS: We examined associations of polygenic scores (PGSs) for general addiction risk, environmental factors, and their joint interactions with PSU initiation among 11,868 adolescents (aged 11-15 years) from the Adolescent Brain and Cognitive Development study. PSU status was assessed through interviews and toxicology screenings.RESULTS: Our sample included 7,898 adolescents (mean age 12.9 [0.6] years; 4,150 [53%] male). Of these, 541 (6.8%) had initiated single substance use (SSU), and 162 (2.1%) reported PSU). PGSs for general addiction risk were significantly associated with PSU (Odds Ratios [OR]=1.62, 95% CI=1.30-2.01) but not with SSU. Key environmental risk factors for PSU included prenatal substance use and peer victimization, whereas protective factors included planned pregnancy and positive family dynamics. Notably, gene-environment interaction analyses revealed that peer victimization (OR=2.4, 95% CI=1.4-4.2), prenatal substance use (OR=2.1, 95% CI=1.2-3.6), and substance availability (OR=2.3, 95% CI=1.3-3.9) substantially increased PSU risk among adolescents with high genetic susceptibility, while having minimal influence at low genetic risk levels (all < 0.05 after multiple testing correction).CONCLUSIONS: This study provides novel evidence linking polygenic risk to PSU in early adolescence and highlights PSU as a more severe manifestation of substance use liability driven by heightened genetic vulnerability and adverse environmental exposures.