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Youth living with HIV have sub-optimal rates of adherence to antiretroviral therapy (ART). Mindfulness instruction interventions have shown promise for improving medication adherence, but the effects and mechanisms of these interventions are still being explored among people living with HIV, including youth. In the context of a randomized controlled trial of the efficacy of a Mindfulness-Based Stress Reduction (MBSR) program on ART adherence and viral suppression among youth living with HIV, we conducted 44 iterative, semi-structured, in-depth interviews with 20 study participants (13–24 years) recruited from clinics at two academic centers in Baltimore, Maryland. Interviews explored the social context and psychosocial dynamics of ART adherence in the context of the MBSR intervention, compared with those in a control arm. We employed thematic content analysis to systematically code and synthesize textual interview data. Participants’ challenges with ART adherence were often situated within an ongoing process of working to manage HIV as a stigmatized, chronic condition in addition to other intersecting social stigmas, inequalities, and stressors. Participation in the MBSR program and related group support allowed participants to non-judgmentally observe and accept difficult thoughts, feelings, and experiences associated with living with HIV and taking ART, which facilitated greater reported adherence. Mindfulness training may stimulate new perspectives and understanding, including greater self- and illness-acceptance among youth living with HIV, leading to improved HIV outcomes.