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Objective: A long-term medication adherence project was designed and implemented in an urban HIV clinic to address antiretroviral medication adherence. Design and Methods: We conducted a prospective study of patients on long-term antiretroviral therapy. Referred patients were on antiretroviral agents at least six months and had two consecutive detectable viral loads. A standarized form was utilized to assess medication adherence, including patient report, practitioner assessed barriers, and pharmacy refill history. Individualized interventions were developed to accommodate patient needs. Results: Seventy-eight patients met inclusion criteria for a total of 81 cases per study protocol. The majority of cases had an identifiable cause related to missed and/or mistimed doses. Following adherence interventions, 51 of the 81 cases (63%) experienced a successful outcome. In addition, 16 of the 27 cases (59%) without an identifiable cause became undetectable following intervention. Conclusions: This novel approach demonstrates that a proactive method for addressing barriers to long-term medication adherence yields improved patient understanding and preservation of treatment regimens.