Global AIDS programs such as the US President's Emergency Plan for AIDS Relief (PEPFAR) face a challenging health care management transition. HIV care must evolve from vertically-organized, externally-supported efforts to sustainable, locally controlled components that are integrated into the horizontal primary health care systems of host nations. We compared four southern African nations in AIDS care, financial, literacy, and health worker capacity parameters (2005 to 2009) to contrast in their capacities to absorb the huge HIV care and prevention endeavors that are now managed with international technical and fiscal support. Botswana has a relatively high national income, a small population, and an advanced HIV/AIDS care program; it is well poised to take on management of its HIV/AIDS programs. South Africa has had a slower start, given HIV denialism philosophies of the previous government leadership. Nonetheless, South Africa has the national income, health care management, and health worker capacity to succeed in fully local management. The sheer magnitude of the burden is daunting, however, and South Africa will need continuing fiscal assistance. In contrast, Zambia and Mozambique have comparatively lower per capita incomes, many fewer health care workers per capita, and lower national literacy rates. It is improbable that fully independent management of their HIV programs is feasible on the timetable being contemplated by donors, nor is locally sustainable financing conceivable at present. A tailored nation-by-nation approach is needed for the transition to full local capacitation; donor nation policymakers must ensure that global resources and technical support are not removed prematurely.