This study examined the relationship between substance use, mental health problems, and HIV sexual risk behaviors among a sample of foster care adolescents. Data were collected through structured baseline interviews with 320 adolescents (ages 15 to 18 years) who resided in foster care placements and participated in a larger evaluation study of an HIV prevention program. Final logistic regression models indicated that delinquent behavior and marijuana use were the most significant predictors of engaging in any one HIV risk behavior. Adolescents who reported delinquent behaviors, alcohol use, and marijuana use and who were female were more likely than their counterparts to engage in vaginal sex without using a condom. Future research is needed to further identify risk and protective factors for substance use, mental health problems, and HIV sexual risk behaviors among adolescents in foster care. HIV prevention efforts for these vulnerable adolescents should target those with substance use and delinquent behaviors.