Objective To apply a social ecological model to explore the psychosocial factors prospectively associated with longitudinal adherence to antiretroviral treatment in youth perinatally infected with HIV. Methods Randomly selected youth, age 8 to <19 years old, completed cognitive testing and psychosocial questionnaires at baseline as part of a multisite protocol (N = 138). A validated caregiver-report measure of adherence was completed at baseline and 24 and 48 weeks after baseline. Results In multivariate analysis, youth awareness of HIV status, caregiver not fully responsible for medications, low caregiver well-being, adolescent perceptions of poor caregiver–youth relations, caregiver perceptions of low social support, and African American ethnicity were associated with nonadherence over 48 weeks. Conclusions Interventions focusing on caregivers and their interactions with the individual youth and extrafamilial system should be prioritized for prevention and treatment efforts to address nonadherence during the transition into adolescents.