In a sample of perinatally HIV-infected (PHIV+) and perinatally HIV-exposed, uninfected (PHEU) adolescents, we examined the co-occurrence of behavioral health risks including mental health problems, onset of sexual and drug use behaviors, and (in PHIV+ youth) nonadherence to antiretroviral therapy (ART). Participants, recruited from 2007 to 2010, included 349 youth, ages 10-16 years, enrolled in a cohort study examining the impact of HIV infection and ART. Measures of the above behavioral health risks were administered to participants and primary caregivers. Nearly half the participants met study criteria for at least one behavioral health risk, most frequently, mental health problems (28%), with the onset of sexual activity and substance use each reported by an average of 16%. Among the sexually active, 65% of PHIV+ and 50% of PHEU youth reported unprotected sex. For PHIV +youth, 34% reported recent ART nonadherence, of whom 45% had detectable HIV RNA levels. Between 16% (PHIV+) and 11% (PHEU) of youth reported at least two behavioral health risks. Older age, but not HIV status, was associated with having two or more behavioral health risks versus none. Among PHIV+ youth, living with a birth mother (versus other caregivers) and detectable viral load were associated with co-occurrence of behavioral health risks. In conclusion, this study suggests that for both PHIV+ and PHEU youth, there are multiple behavioral health risks, particularly mental health problems, which should be targeted by service systems that can integrate prevention and treatment efforts.