The HIV epidemic in sub-Saharan Africa represents an obstacle to productive employment and economic development. Employers in the region are experiencing severe staff shortages, reduced productivity, and increased costs because of protracted ill health and death among their workforce. The scale of the problem has not been fully estimated and the extent to which it could be ameliorated by control measures including effective treatment of opportunistic infections is not well known. Employers and employees (n = 108) in seven Zambian firms were interviewed to assess direct and indirect costs of illness to the firms. Information was collected on diagnosis and treatment received, duration of illness, time off, and strategies adopted to compensate for absent workers using a combination of questionnaires, structured interviews and focus group discussions. The main causes of ill health were tuberculosis (TB) (46.8%), diarrhea (12.9%), and sexually transmitted diseases (STDs; 5.8%). Annual treatment costs to the firm ranged from Zambia Kwacha (K) 60,000 to 405,000 per person treated. Other firm costs included productivity losses because of ill health, paid sick leave, the cost of employee replacement, and funerals. Employees incurred K 67,773 on average per illness episode. The most common causes of ill health were those most frequently associated with HIV. They can be easily but were often ineffectively treated. Improving disease management would thus reduce wastage and costs both to employer and employee. The extent of the impact in these firms shows the need for the private sector to adopt a stronger role in prevention and care. Further research is required to assess what recommended treatment options might be, how they could be financed, and the extent of the economic impact of HIV on firms. This would foster the development of more appropriate responses to the epidemic in Zambia and the region as a whole.