Babesia is a red cell parasite endemic in the Northeastern and upper Midwestern regions of the US and responsible for the disease referred to as babesiosis. The parasite is naturally transmitted by the bite of an infected tick but may also be transmitted by blood transfusion. Infection may be asymptomatic or cause non-specific symptoms: fever, fatigue, headache, and muscle pain. In some cases, the disease can be severe, especially in those with a compromised immune system, hemoglobin-related diseases (such as sickle cell disease), and those lacking a spleen. The Red Cross began blood donation screening for Babesia microti, the species most common in the US, under an investigational protocol in June 2012 in the New England area and upper Midwest. Donors who consented to investigational screening were tested by two tests: an individual donation NAT assay (polymerase chain reaction, PCR) and an antibody assay, the latter using an indirect immunofluorescence assay (IFA). Reactive donations were further tested by various methods to confirm infection, including a more sensitive PCR and western blot. The frequency of detecting an infected donor in highly endemic areas where screening occurred was about 1 per 250 donations using both antibody and NAT. In the absence of screening, the estimated risk of transfusion-transmitted babesiosis is generally about 1 per 100,000 unscreened donations in an endemic state but maybe as high as 1 per 18,000 in highly endemic counties within an endemic state. Unscreened blood collected in a highly endemic area is 16 times more likely to be infectious than screened blood (where screened blood has not been associated with a transmission). In May 2018, the Red Cross began testing from whole blood samples using a NAT assay that detects the main four species of babesia pathogenic to humans. The assay, now FDA licensed, detects ribosomal RNA of the parasite following red cell lysis, significantly increasing sensitivity and obviating the need for antibody testing. Because the lysis step releases thousands of babesia RNA copies, mini-pool testing can be performed (MPs of 16). If a reactive donation is identified, testing is repeated, and a sample is sent for antibody testing by IFA. In May 2019, the FDA released guidance to test all donations collected in the following 14 states considered babesia endemic or contiguous to an endemic state: Maine, Vermont, New Hampshire, Connecticut, Massachusetts, New York, New Jersey, Delaware, Rhode Island, Maryland, Pennsylvania, Virginia, Minnesota, and Wisconsin and in the District of Columbia. Red Cross implemented the guidance for testing in May 2020.