BACKGROUND The Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) is a 7-year multicenter transfusion safety research initiative launched in 2011 by the National Heart, Lung, and Blood Institute. METHODS The domestic component involves four blood centers, 12 hospitals, a data coordinating center, and a central laboratory. The international component consists of distinct programs in Brazil, China, and South Africa, which involve US and in-country investigators. RESULTS REDS-III is using two major methods to address key research priorities in blood banking and transfusion medicine. First, there will be numerous analyses of large "core" databases; the international programs have each constructed a donor and donation database while the domestic program has established a detailed research database that links data from blood donors and their donations, the components made from these donations, and data extracts from the electronic medical records of the recipients of these components. Second, there are more than 25 focused research protocols involving transfusion recipients, blood donors, or both that either are in progress or are scheduled to begin within the next 3 years. Areas of study include transfusion epidemiology and blood utilization, transfusion outcomes, noninfectious transfusion risks, human immunodeficiency virus-related safety issues (particularly in the international programs), emerging infectious agents, blood component quality, donor health and safety, and other donor issues. CONCLUSIONS It is intended that REDS-III serve as an impetus for more widespread recipient and linked donor-recipient research in the United States as well as to help assure a safe and available blood supply in the United States and in international locations.