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Botswana has the highest rate of HIV infection in the world, estimated at 36% among the population aged 15-49 years. To improve antiretroviral (ARV) treatment delivery, we conducted a cross-sectional study of the social, cultural, and structural determinants of treatment adherence.We used both qualitative and quantitative research methodologies, including questionnaires and interviews with patients receiving ARV treatment and their health care providers to elicit principal barriers to adherence. Patient report and provider estimate of adherence (≥95% doses) were the primary outcomes.One hundred nine patients and 60 health care providers were interviewed between January and July 2000; 54% of patients were adherent by self-report, while 56% were adherent by provider assessment. Observed agreement between patients and providers was 68%. Principal barriers to adherence included financial constraints (44%), stigma (15%), travel/migration (10%), and side effects (9%). On the basis of logistic regression, if cost were removed as a barrier, adherence is predicted to increase from 54% to 74%.ARV adherence rates in this study were comparable with those seen in developed countries. As elsewhere, health care providers in Botswana were often unable to identify which patients adhere to their ARV regimens. The cost of ARV therapy was the most significant barrier to adherence.