AbstractBackgroundRho(D) immune globulin (RhIg) is used to reduce RhD alloimmunization in pregnancy. This study describes potential causes for RhD alloimmunization after the development and implementation of RhIg.Study Design and MethodsThis retrospective descriptive study investigated RhD‐negative patients born in 1965–2005 with anti‐D newly identified during 2018–2022. Transfusion, pregnancy, intravenous drug abuse, and transplantation were considered potential alloimmunization sources.ResultsThere were 1200 study patients (852 females; 348 males) at 30 institutions in 5 countries (USA, Canada, UK, New Zealand, Brazil). Most patients had a single potential source of alloimmunization identified (857/1200, 71%), most commonly pregnancy among females (537/852, 63%) and transfusion among males (180/348, 52%). When multiple potential sources were included, males were more likely than females to have a history of transfusion (235/348 [68%] vs. 149/852 [17%], p < .0001) and confirmed or suspected intravenous drug abuse (100/348 [29%] vs. 138/852 [16%], p < .0001). Among females with a history of pregnancy, 119/718 (17%) had healthcare access issues, 120/718 (17%) had pregnancy in a country where they may not have received RhIg, and 21/718 (3%) refused RhIg. Among patients with a history of transfusion, males were more likely than females to have received RhD‐positive red blood cells or whole blood (143/235 [61%] vs. 30/149 [20%], p < .0001) and/or platelets (84/235 [36%] vs. 19/149 [13%], p < .0001).DiscussionPregnancy was the most frequently identified potential source of RhD alloimmunization among females. Transfusion was most frequent in males. Intravenous drug abuse as a common potential source among patients with RhD alloimmunization merits further study.