Despite advances in HIV medicine, adherence presents as a barrier to effective treatment for youth. We designed this study to assess medication knowledge, adherence, and factors affecting adherence in youth with HIV. Participants were 72 youth ages 13 to 24 years with perinatally or behaviorally acquired HIV. Demographic data were collected and a self-report adherence interview was administered. Interviews were audio-recorded to allow for qualitative data analysis. Self-reported adherence varied depending on the framing of questions, with participants reporting greater adherence when asked how many doses they had missed within the past 7 days compared to results from a 7-day recall interview. At least 74% of the sample said they sometimes forgot to take their medication. A taxonomic approach to the qualitative analysis revealed internal and external facilitators and barriers to adherence. Findings suggest a need for education and provider support to include strategies to improve adherence.