Youth living with HIV in sub-Saharan Africa face numerous challenges in adhering to HIV treatment. The AIDS epidemic has left many of these youth orphaned due to AIDS-related death of one or both parents. It is imperative to understand the family context of youth living with HIV in order to develop responsive interventions to improve adherence to antiretroviral therapy. We conducted qualitative in-depth interviews with 17 HIV-infected AIDS orphans, ages 13–24 years, screened positive for mental health difficulties according to the Patient Health Questionaire-9 (PHQ-9) or UCLA PTSD Reaction Index (PTSD-RI), and receiving outpatient HIV care at an adolescent medical clinic in Moshi, Tanzania. Treatment-related support varied by orphan status. Paternal orphans cared for by their biological mothers and maternal orphans cared for by grandmothers described adherence support such as assistance taking medication and attending clinic. Double orphans did not report adherence support. Several maternal and double orphans faced direct interference from caregivers and household members when they attempted to take their medications. Caregivers play a significant role in treatment adherence and must be considered in interventions to increase medication adherence in HIV-infected orphans. Findings from this study informed caregiver participation in Sauti ya Vijana (The Voice of Youth), a mental health intervention for youth living with HIV in Tanzania.