Objective: To examine the prevalence and biopsychosocial predictors of suboptimal virologic response to highly active antiretroviral therapy (HAART) among human immunodeficiency virus-infected adolescents. Design: Population-based cohort study. Setting: Sixteen academic medical centers across 13 cities in the United States. Participants: One hundred fifty-four human immunodeficiency virus-infected adolescents who presented for at least 2 consecutive visits after initiation of HAART. Main Outcome Measures: Viral load (plasma concentration of human immunodeficiency virus RNA) and CD4+ lymphocyte count. Results: Of the 154 adolescents enrolled in the study, 50 (32.5%) demonstrated early and sustained virologic suppression while receiving HAART. The remaining 104 adolescents (67.5%) had a poor virologic response. Adequate adherence (>50%) - reported by 70.8% of respondents - was associated with 60% reduced odds of suboptimal virologic suppression in a multivariable logistic regression model (adjusted odds ratio=0.4; 95% confidence interval, 0.2-1.0). Exposure to suboptimal antiretroviral therapy prior to HAART, on the other hand, was associated with more than 2-fold increased odds of suboptimal virologic response (adjusted odds ratio=2.6; 95% confidence interval, 1.1-5.7). Conclusions: Fully two-thirds of human immunodeficiency virus-infected adolescents in the current study demonstrated a suboptimal virologic response to HAART. Nonadherence and prior single or dual antiretroviral therapy were associated with subsequent poor virologic responses to HAART. These predictors of HAART failure echo findings in pediatric and adult populations. Given the unique developmental stage of adolescence, age-specific interventions are indicated to address high rates of nonadherence and therapeutic failure. ©2009 American Medical Association. All rights reserved.