OBJECTIVES: Past studies have indicated that regimen compliance is associated with virological failure which, in turn, impacts the cost of treating HIV/AIDS. We calculated the per-patient cost of HIV/AIDS treatment in two African countries based on recently reported compliance studies and treatment costs. METHODS: Patient compliance rates from recent studies in two African countries (South Africa and Uganda) were paired with compliance-specific virologic failure rates from the literature to estimate the rates of treatment failure in each country. Any patient with virologic failure was assumed to receive second-line therapy. As a base case, we used published estimates of HIV/AIDS annual per patient drug costs of $292 (in 2003 U.S.D.) in Uganda and $400 in South Africa for patients not experiencing virological failure and $1594 (Uganda) and $1203 (South Africa) for patients that do experience virological failure. The average annual per-patient drug cost was estimated for the two countries from a non-governmental organization (NGO) perspective. Sensitivity analyses were conducted on drug prices and compliance rates. RESULTS: Given each country's compliance rates, the average virological failure rate was projected to be 39% in Uganda and 68% in South Africa. The average drug cost per patient was estimated to be $914 and $801 per year in South Africa and Uganda, respectively. If compliance rates were varied by +/- 25% of base case values, cost estimates ranged from $841 to $987 for South Africa and from $756 and $935 for Uganda. Similarly, if drug costs were varied by +/- 25%, cost estimates ranged from $685 to $1142 for South Africa and from $601 to $1002 for Uganda. CONCLUSION: Patient compliance is an important determinant of per-patient costs and overall budgets for the drug cost of treating HIV/AIDS in Africa. Considering only first and second-line unit costs does not accurately reflect overall treatment costs.