BACKGROUND: Evidence for cost-effectiveness of interventions for HIV/AIDS in Africa is fragmentary. Cost-effectiveness is, however, highly relevant. African governments face difficult choices in striking the right balance between prevention, treatment, and care, all of which are necessary to deal comprehensively with the epidemic. Reductions in drug prices have raised the priority of treatment, though treatment access is restricted. We assessed the existing cost-effectiveness data and its implications for value-for-money strategies to combat HIV/AIDS in Africa. METHODS: We undertook a systematic review using databases and consultations with experts. We identified over 60 reports that measured both the cost and effectiveness of HIV/AIDS interventions in Africa. 24 studies met our inclusion criteria and were used to calculate standardised estimates of the cost (US$ for year 2000) per HIV infection prevented and per disability-adjusted life-year (DALY) gained for 31 interventions. FINDINGS: Cost-effectiveness varied greatly between interventions. A case of HIV/AIDS can be prevented for $11, and a DALY gained for $1, by selective blood safety measures, and by targeted condom distribution with treatment of sexually transmitted diseases. Single-dose nevirapine and short-course zidovudine for prevention of mother-to-child transmission, voluntary counselling and testing, and tuberculosis treatment, cost under $75 per DALY gained. Other interventions, such as formula feeding for infants, home care programmes, and antiretroviral therapy for adults, cost several thousand dollars per infection prevented, or several hundreds of dollars per DALY gained. INTERPRETATION: A strong economic case exists for prioritisation of preventive interventions and tuberculosis treatment. Where potentially exclusive alternatives exist, cost-effectiveness analysis points to an intervention that offers the best value for money. Cost-effectiveness analysis is an essential component of informed debate about priority setting for HIV/AIDS.