BACKGROUND: Blood transfusions carry the risk of transmitting infections. This risk has been studied in detail in high-income countries but not in sub-Saharan Africa. This study estimates the risks of acquiring human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) from a single unit of blood in sub-Saharan Africa. STUDY DESIGN AND METHODS: A mathematical model was constructed to quantify transfusion risks across 45 sub-Saharan African countries using three components: the risk of a contaminated unit entering the blood supply, the risk that the unit will be given to a susceptible patient, and the risk that receipt of the unit will lead to infection in the recipient. Variables included prevalence of infection in donors, extent of blood testing, test sensitivity, and susceptibility of recipients. Data from the World Health Organization (WHO) African Region and a systematic review of the literature were used to parameterize the model. Uncertainty in the risk estimates was quantified using probabilistic sensitivity analysis. RESULTS: The median overall risks of becoming infected with HIV, HBV, and HCV from a blood transfusion in sub-Saharan Africa were 1, 4.3, and 2.5 infections per 1000 units, respectively. If annual transfusion requirements projected by the WHO were met, transfusions alone would be responsible for 28,595 HBV infections, 16,625 HCV infections, and 6650 HIV infections every year. Sensitivity analysis suggests that the true risks may be even higher. CONCLUSIONS: This study is the first to systematically quantify the risks of transfusion-transmitted infections across sub-Saharan Africa. Although the results are limited by the quality and quantity of available data, these may be the most reliable estimates at this time.