Globally, data on antenatal blood transfusion practices are scarce. We sought to characterize the epidemiology of antenatal transfusion in South Africa. A cross-sectional study was conducted of women who were transfused during pregnancy (>48 hr before anticipated delivery) at two hospitals in Durban and Soweto in 2014 to 2015. Medical record data on demographics, obstetric history, anemia, HIV status, and indications for blood transfusion were abstracted. The records on a total of 560 transfused pregnant women were evaluated; mean age was 28 years, 98% were of black African ethnicity, and 28% were HIV positive. At time of transfusion, one-half were in the first trimester. Hemorrhage was noted in 76% of women, most of which was associated with abortion (67%) or ectopic pregnancy (27%). Most women were transfused with red blood cells (RBCs; median, 2 units); 14% of women were transfused with plasma and 2% with platelets. Median pre- and posttransfusion hemoglobin levels were 6.9 g/dL and 9.2 g/dL, respectively; the latter differed by hospital (8.7 g/dL vs. 9.5 g/dL; p < 0.01). Hemorrhage was associated with missing HIV status, lower gestational age, and transfusion of 3 or more RBC units (all p < 0.01). In contrast, diagnoses of anemia (Soweto only) were associated with HIV infection, later gestational age, and lower (<3 units) RBC dose (all p < 0.01). Abortion and ectopic pregnancy with associated hemorrhage were the leading indications for antenatal transfusion and were concentrated in early gestation. By contrast, anemia was associated with HIV infection and transfusion in the third trimester.