Background: Research is yet to elucidate adolescent polysubstance use profiles among youth with early-onset cannabis use (CU; ≤15 years). The present study aimed to fill this gap in the literature and determine whether CU outcomes in early adulthood are best explained by early-onset CU per se, or by its resulting polysubstance use profiles. Methods: Participants were N = 794 youth (56% females) from the Québec Longitudinal Study of Child Development, who reported lifetime CU by age 21. Participants were stratified into early-onset (n = 349), later adolescent-onset (16–18 years; n = 359), and adult-onset (≥19 years; n = 86) CU groups. Self-reported substance use was collected from the early-onset CU group at age 15 and 17, while CU frequency and problem CU were assessed for all participants at age 21. Results: Repeated measures latent profile analyses revealed four polysubstance use profiles among youth in the early-onset CU group: (1) light (54%); (2) escalating (13%); (3) frequent (without cigarettes; 14%); (4) frequent (with cigarettes; 19%). Only youth in the early-onset CU group who followed an escalating or frequent (with cigarettes) adolescent polysubstance use profile had consistently greater CU frequency and problem CU at 21 years, compared to youth in the later adolescent-onset (16–18 years), or adult-onset (≥19 years) CU groups (β range = 0.13 to.40; Cohen’s f2 range = 0.02 to 0.12). Conclusions: Youth with early-onset CU are not a single homogenous group, but rather follow unique polysubstance use profiles that are differentially associated with risk for future problem CU.Read less <