Results of the study suggest that perinatally human immunodeficiency virus (HIV)-infected (PHIV+) and perinatally HIV exposed but uninfected (PHIV-) youth were engaging in sexual behaviors and substance use with no differences between PHIV+ and PHIV- groups. Although an association between HIV status and mental health symptoms or risk behaviors was not found, the findings underscore that youth and caregiver mental health might play critical roles in influencing the risk behaviors of perinatally HIV-exposed youths. Youth and caregiver mental health problems were related to sex and drug use risk behaviors in PHIV+ and PHIV- youth. The data suggest that incorporating HIV prevention interventions into ongoing mental health programs might be an effective strategy to reach PHIV+ youth and reduce HIV transmission risk. As PHIV+ youth enter adolescence, they were at high risk for poor behavioral and health outcomes. The purpose of this study was to examine the relations between youth mental health problems and sexual and substance use risk behavior, the impact of caregiver mental health and family functioning on youth mental health and risk behavior outcomes, and the role of youth HIV status in this process. Primarily African-American and Latino, participants in the study were interviewed to assess child sexual and drug risk behavior, child and caregiver mental health, and family functioning. Figure, tables, and references