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Controlled trials that determine which interventions can significantly improve adherence to combination antiretroviral regimens are urgently needed. Rates of adherence to the regimens are often sub-optimal, and while a variety of factors that are predictive or associated with antiretroviral adherence have been identified, few research findings are reported of interventions that effectively promote adherence and improve health outcomes. Further, the mechanisms by which interventions promote antiretroviral adherence are not well understood. Maximizing adherence and achieving the full potential of the antiretroviral therapies demand multidimensional initiatives that address complex behavioural and biomedical issues. A model drawn from self-regulation theory and empirical data to explain antiretroviral medication adherence is proposed.