AIMS: Internalizing symptoms are theorized to lead to substance use (SU) via a tendency to use substances to cope with or self-medicate negative feelings and emotions; however, empirically, this association is mixed, pointing to the existence of moderating factors. The present study aimed to examine how self-, teacher-, and father-reported attention-deficit/hyperactivity disorder hyperactivity-impulsivity symptoms (ADHD-HI) and sex, moderated the association between self-reported internalizing symptoms and SU, in early adolescence. METHODS: Cross-sectional data obtained at 13 years of age, drawn from the Quebec Longitudinal Study of Child Development (N = 1,424; 53 % female). Alcohol, cigarette, and cannabis use, and internalizing and ADHD-HI symptoms were assessed. RESULTS: There was a significant three-way interaction between internalizing, ADHD-HI, and sex, for cigarette use, with Bayes factor (BF) indicating very strong evidence for an effect (BF = 48.40). While the three-way interaction for cannabis use did not reach statistical significance (self-report: p <.066; father-report: p <.053), BF indicated substantial evidence for an effect (self-report: BF = 3.54; father-report: BF = 9.08). Further analyses revealed internalizing was associated with cigarette and cannabis use only among females with high ADHD-HI symptoms (cigarette use: β = 0.15, SE = 0.04, 95 %CI [0.07, 0.22]; cannabis use (self-reported ADHD-HI): β = 0.14, SE = 0.06, 95 %CI [0.04, 0.25]; cannabis use (father-reported ADHD-HI): β = 0.21, SE = 0.10, 95 %CI [0.01, 0.41]). CONCLUSIONS: Findings aid in clarifying the inconsistent relationship between internalizing symptoms and SU among adolescent females by underscoring the moderating role of ADHD-HI. Further, findings also support a growing body of literature which highlights the need for both self- and adult-informants (i.e., teacher and parent) in assessing ADHD-HI symptoms in females.Read less <