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Adherence to antiretroviral medications has been shown to be an important factor in predicting viral suppression and clinical outcomes. The objective of this analysis was to assess the cost-effectiveness of a nursing intervention on antiretroviral adherence using data from a randomized controlled clinical trial as input to a computer-based simulation model of HIV disease. For a cohort of HIV-infected patients similar to those in the clinical trial (mean initial CD4 count of 319 cells/mm3), implementing the nursing intervention in addition to standard care yielded a 63% increase in virologic suppression at 48 weeks. This produced increases in expected survival (from 94.5 to 100.9 quality-adjusted life months) and estimated discounted direct lifetime medical costs ($253,800 to $261,300). The incremental cost-effectiveness ratio for the intervention was $14,100 per quality-adjusted life year gained compared with standard care. Adherence interventions with modest effectiveness are likely to provide long-term survival benefit to patients and to be cost-effective compared with other uses of HIV care funds.