Incorrect or inconsistent adherence to antiretroviral therapy (ART) compromises the effectiveness of medications and the patient’s chances of achieving viral suppression; near-perfect (>95%) compliance is required for both immediate and long-term clinical success. This report presents a systematic review of a multicomponent intervention to address adherence to ART and explores whether this intervention, when compared with standard care, resulted in improved ART adherence. Eleven randomized controlled trial studies published between 1999 and 2008 were reviewed. Seven of these demonstrated a beneficial effect from multicomponent intervention, which primarily incorporated individual education and one to three additional interventions. Interventions targeting the improvement of the patient's medication management skills were particularly successful. However, because of incongruent results across studies, it could not be determined whether improved adherence extended to improved virologic or immunologic outcomes. There is a need for standardization and increased methodological rigor in the execution of adherence trials.