Challenges to the adherence to combination antiretroviral therapy among the pediatric population should be understood in the context of the trajectories of families, their interaction with healthcare services, and their access to material and symbolic goods. The present study analyzed individual, institutional and social factors that might be associated with the caregivers' role in the treatment adherence of children and adolescents living with HIV (CALHIV). Based on semi-structured interviews and questionnaires applied to 69 caregivers seen at pediatric AIDS services of five Brazilian macro-regions, we observed that adherent caregivers had better acceptance of diagnosis and treatment, were less likely to face discrimination and social isolation secondary to AIDS-related stigma and tended to believe in the efficacy of treatment, and to be more optimistic about life perspectives of CALHIV. Interventions aiming to improve adherence and to promote the health of CALHIV should take in consideration the interplay of such different factors.