BackgroundYoung adults with a history of foster care have higher risk for substance use disorders. Social systems can deliver substance use prevention to youth; however, the timing of intervention delivery and how needs differ for youth in foster care are unclear. ObjectiveTo compare initiation and rates of substance use among adolescents in foster care to demographically similar adolescents never in foster care as identified by the healthcare system, and identify factors associated with increased substance use. Participants and settingYouth in foster care (n = 2787, ages 10–20, inclusive) and demographically matched youth never in foster care (n = 2787) were identified using linked child welfare and electronic health records from a single pediatric children's hospital and county over a five-year period (2012–2017). MethodsAll healthcare encounters were reviewed and coded for substance use by type (alcohol, tobacco, cannabis, other). Age of first reported or documented substance use was also captured. Demographic and child welfare information was extracted from administrative records. Survival and logistic regression models were estimated. ResultsIn adjusted models, youth in foster care initiated substance use at earlier ages (HR = 2.50, p < .01) and had higher odds of engaging in use (AOR = 1.54; p < .01) than youth never in care. By age 12, substance use initiation was more likely while youth were in foster care than when they were not in foster care (HR = 1.42, p < .01). Placement stability and family care settings reduced odds of lifetime substance use. ConclusionsFoster care placement is associated with substance use. Screening may be important for prevention.