Abstract Survival among perinatally infected children and youth with HIV has been greatly extended since the advent of highly active antiretroviral therapies. Yet, adherence to HIV medication regimens is suboptimal and decreases as children reach adolescence. This paper reports on a qualitative study examining psychosocial factors associated with adherence among perinatally infected youth ages 10-16 years. The study was based on in-depth interviews with a sample of 30 caregivers participating in a comprehensive health care program in New York City serving families with HIV. A subsample comprising 14 caregivers of children ages 10 and above is the focus of this paper. The analysis identified a number of themes associated with the psychosocial context of managing adherence among older children. Maintaining adherence was an ongoing challenge and strategies evolved as children matured. Regimen fatigue and resistance to taking the medications were major challenges to maintaining adherence among the oldest children. In other cases, caregivers developed a kind of partnership with their child for administering the medications. Disclosure to the child of his or her HIV status was used as a strategy to promote adherence but seemed to be effective only under certain circumstances. Social support appeared to have an indirect influence on adherence, primarily by providing caregivers with temporary help when needed. Health care professionals were an important source of disclosure and adherence support for parents. The study illustrates the interplay of maturational issues with other contextual psychosocial factors as influences on adherence among older children and adolescents.