This study examines risk factors for substance involvement for youths involved with the child welfare (CW) system. In addition to common risk factors examined in general population studies; this research examines risk factors unique to youths in the CW system, including age at entry into CW and number of out-of-home placements. Participants included 214 youths ages 13 to 18, randomly sampled from youths active to CW in San Diego County, California. Severity of substance involvement was assessed through structured diagnostic interviews determining lifetime substance use, abuse, and dependence. Hierarchical regression analyses including demographics, psychosocial variables, maltreatment history, CW placement variables, and the interaction of age at entry into CW and number of out-of-home placements revealed that both common and CW-specific risk factors were associated with the severity of youth substance involvement. Multiple-placement changes, later entry into the CW system, and multiple-placement changes at an older age are associated with higher risk for more serious substance involvement for youths in CW.