As increasing numbers of persons are placed on potentially life-saving combination antiretroviral therapy (cART) in sub-Saharan Africa, it is imperative to identify the psychosocial and social factors that may influence antiretroviral (ARV) medication adherence. Using an 87 question survey, the following data were collected from patients on cART in Botswana: demographics, performance (Karnofsky) score, perceived stigma and level of HIV disclosure, attitudes and beliefs concerning HIV/AIDS, substance and/or drug use, depression, and pharmacy and healthcare provider-related factors. Overall adherence rates were determined by patient self-report, institutional adherence, and a culturally modified Morisky scale. Three hundred adult patients were recruited between April and May 2005. The overall cART adherence rate was 81.3% based on 4 day and 1 month patient recall and on clinic attendance for ARV medication refills during the previous 3 months. Adults receiving cART for 1-6 months were the least adherent (77%) followed by those receiving cART for greater than 12 months (79%). Alcohol use, depression, and nondisclosure of positive HIV status to their partner were predictive of poor adherence rates (p value <0.02). A significant proportion (81.3%) of cART-treated adults were adherent to their prescribed treatment, with rates superior to those reported in resource-rich settings. Adherence rates were poorest among those just starting cART, most likely due to the presence of ARV-related toxicity. Adherence was lower among those who have been treated for longer periods of time (greater than 1 year), suggesting complacency, which may become a significant problem, especially among these long-term cART-treated patients who return to improved physical and mental functioning and may be less motivated to adhere to their ARV medications. Healthcare providers should encourage HIV disclosure to "at-risk" partners and provide ongoing counseling and education to help patients recognize and overcome HIV-associated stigma, alcohol abuse, and depression.