Background. Adolescents represent the fastest growing demographic group of new human immunodeficiency virus (HIV) infections in the United States. At present, there is little information available about their response to therapy. Methods. We studied 120 adolescents infected via high-risk behaviors who began receiving highly active antiretroviral therapy (HAART), to determine their virologic and immunologic response to therapy. Results. Subjects were enrolled at 28 sites of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group. After 16-24 weeks of HAART, 59% of subjects had reproducible undetectable virus loads, according to repeat measurements (virologic success). As enumerated by flow-cytometric analysis, increases in levels of CD4 helper cells (both naive and memory) and decreases in levels of CD8 suppressor cells were observed. Partial restoration of some immunologic parameters for patients who did not achieve virologic success was also observed, but to a more limited extent than for adolescents with virologic success. Adherence to HAART was the only predictor of achieving undetectable virus loads. Conclusions. Adolescents have the capacity to improve their immunologic status with HAART. Lower than expected success in virologic control is related to lack of adherence, and efforts to improve treatment outcome must stress measures to assure adherence to medication.