OBJECTIVES: The risk of HIV, HBV and HCV transmission by blood transfusion in sub Saharan Africa is (very) high compared to the developed world. In this economic evaluation the cost-effectiveness of interventions (donor management, quality of testing, administration and additional tests) improving blood transfusion safety is explored. METHODS: The residual risks of HIV, HBV and HCV transmission were derived for Angola, Benin, Botswana, Côte d'Ivoire, Ethiopia, Kenya, Mozambique, Namibia, Rwanda, Uganda and Zambia from the Global Database on Blood Safety (GDBS; WHO, 2004). Cost-effectiveness ratios of the scenarios were determined by using a decision tree combined with a Markov-model. Health gains and costs were discounted by 3%. RESULTS: The CURRENT (current status) scenario is cost-saving compared to the NONE (no screening, no donor management) scenario, averting 2.0 million Disability Adjusted Life Years (DALYs) and saving US$ 82 million annually. Over 94,000 new HIV infections are averted and 27,674 and 3,360 new HBV and HCV infections respectively. Improving the blood transfusion services from the CURRENT to the BEST (100% screening, no errors) scenario shows a cost-effectiveness ratio of 56.24 US$/DALY averted. With this step 2792 new HIV infections are averted and 1723 and 1622 new HBV and HCV infections respectively. In addition to the BEST scenario, HIV p24 and HCV-antigen testing would avert 19 DALYs at annual net costs of US$ 1.2 million (63,957 US$ /DALY averted). Extending the BEST scenario with single donation multiplex NAT averts 60 DALYs at annual net costs of US$ 9.7 million (161,051 US$/DALY averted). CONCLUSIONS: The current level of blood transfusion safety provided in the included countries is cost-saving. However, maximizing the effects of donor management and screening (coverage and errors) shows a favorable cost-effectiveness ratio. Introducing additional tests alongside antibody testing is associated with high costs and limited reduction of transmission risks.