This study determined the prevalence and patterns of psychological symptoms in adolescents and young adults living with HIV (YLWH) in medical care and relationships between psychological symptoms, route and duration of infection, and antiretroviral treatment (ART). A clinic-based sample of 2032 YLWH (mean age 20.3 years), recruited from 20 adolescent medicine HIV clinics, completed a cross-sectional survey of health behaviors and psychological symptoms using the Brief Symptom Inventory (BSI). Overall, 17.5% of youth reported psychological symptoms greater than the normative threshold on the Global Severity Index. A wide variety of symptoms were reported. The prevalence of clinical symptoms was significantly greater in youth with behaviorally acquired HIV compared to those with perinatally acquired infection (20.6% vs. 10.8%, OR = 2.06 in Multiple Logistic Regression (MLR)), and in those not taking ART that had been prescribed (29. 2% vs. 18.8%, OR = 1.68 in MLR). Knowing one's HIV status for more than one year and disclosure of HIV status were not associated with fewer symptoms. A large proportion of YLWH have psychological symptoms and the prevalence is greatest among those with behaviorally acquired infection. The high rate of psychological symptoms for youth not taking ART that is prescribed is a cause for concern. Symptoms do not appear to be a transient reaction to diagnosis of HIV.