Adherence to antiretroviral regimens continues to be a significant problem in HIV-infected individuals facing a lifetime of therapy. Youth who were infected through perinatal transmission enter into adolescence often with a history of multiple medication regimens. Thus, adherence can be a particularly important issue in these young people, as medication options can often be limited. This was a cross-sectional, observational study to determine the prevalence of personal barriers to adherence and to identify associations among the following barriers in subjects 12 to 24 years old: mental health barriers, self-efficacy and outcome expectancy, and structural barriers. Among the 368 study participants, 274 (74.5%) were adherent and 94 (25.5%) were nonadherent to highly active antiretroviral therapy (HAART). No significant differences were found between adherent and nonadherent subjects according to mental health disorders. Adherence was associated with some but not all structural barriers. Both self-efficacy and outcome expectancy were significantly higher in adherent versus nonadherent subjects (p < 0.0001). In subjects with low self-efficacy and outcome expectancy, adherence differed according to the presence or absence of either mental health or structural barriers, similar to findings in behaviorally- infected adolescents. Interventions that address the breadth and clustering of adherence barriers in adolescents are needed to have the maximum chance for positive effects.