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Objective: Cross-sectional research indicates high rates of mental health concerns among youth with perinatal HIV infection (PHIV), but few studies have examined emerging psychiatric symptoms over time. Methods: Youth with PHIV and peer comparisons who were HIV-exposed but uninfected or living in households with HIV-infected family members (HIV-affected) and primary caregivers participated in a prospective, multisite, longitudinal cohort study. Groups were compared for differences in the incidence of emerging psychiatric symptoms during 2 years of follow-up and for differences in psychotropic drug therapy. Logistic regression models were used to evaluate the association of emerging symptoms with HIV status and psychosocial risk factors. Results: Of 573 youth with study entry assessments, 92% attended at least 1 annual follow-up visit (PHIV: 296; comparisons: 229). A substantial percentage of youth who did not meet symptom criteria for a psychiatric disorder at study entry did so during follow-up (PHIV = 36%; comparisons = 42%). In addition, those who met criteria at study entry often met criteria during follow-up (PHIV = 41%; comparisons = 43%). Asymptomatic youth with PHIV were significantly more likely to receive psychotropic medication during follow-up than comparisons. Youth with greater HIV disease severity (entry CD4% <25% vs 25% or more) had higher probability of depression symptoms (19% vs 8%, respectively). Conclusions: Many youth in families affected by HIV are at risk for development of psychiatric symptoms.