Psychopathologic traits that arise in adolescence may increase proneness to substance use uptake as well as channel the familial transmission of substance use. Poly use is a common pattern of substance use in youth. To identify a parsimonious model of familial transmission of substance use, the current study tested whether anhedonia-a psychopathologic endophenotype manifested as the inability to experience pleasure-mediates the association of family history of substance use (FHS) with polysubstance use patterns across midadolescence. High school students (N = 3,392) in Los Angeles, CA, completed 4 semiannual surveys of mental health and substance use from ages 14- to 16-years-old. Use and co-use of cigarettes, alcohol, and marijuana across the 4 waves were reduced to 4 homogenous classes using parallel process growth mixture modeling: (a) abstainers (N = 1,629, 48.0%); (b) experimenters (N = 1,293, 38.1%); (c) polysubstance using marijuana escalators (N = 210, 6.2%); and (d) heavy polysubstance using cigarette escalators (N = 126, 3.7%). FHS was positively associated with membership in each of the three substance using trajectory groups (vs. the abstainers group). After adjusting for depressive symptoms and other covariates, associations of FHS with membership in the polysubstance using marijuana escalators group and with the heavy polysubstance using cigarette escalators group (in comparison with the abstainers or experimenters groups) were each significantly mediated by anhedonia in youth age 14 (the proportion mediated by anhedonia: 0.33-0.42). Etiology research and intervention addressing anhedonia may have value for understanding and preventing the familial transmission of adolescent polysubstance use patterns. (PsycINFO Database Record (c) 2019 APA, all rights reserved).