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<b><i>Introduction:</i></b> Uncrossmatched ABO-compatible red blood cells (RBCs) are generally recommended in patients with life-threatening massive bleeding. There is little data regarding RBC transfusion when patients are transfused against clinically significant alloantibodies because compatible RBCs are not immediately available. <b><i>Methods/Patients:</i></b> All patients reviewed in this study (<i>n</i> = 6,109) required emergency blood transfusion and were treated at the Charité – Universitätsmedizin Berlin between 2001 and 2015. Primary uncrossmatched O Rh(D)-positive or -negative RBC units were immediately transfused prior to complete regulatory serological testing including determination of ABO group, Rhesus antigens, antibody screening, and crossmatching. <b><i>Results:</i></b> Without any significant change in the protocol of emergency transfusion of RBCs, a total of 63,373 RBC units were transfused in 6,109 patients. Antibody screening was positive in 413 patients (6.8%), and 19 of these patients received RBC units against clinically significant alloantibodies. None of these patients appeared to have developed significant hemolysis, and only one patient with anti-D seems to have developed signs of insignificant hemolysis following the transfusion of three Rh(D)-positive units. One patient who had anti-Jk^a received unselected units and did not develop a hemolytic transfusion reaction. <b><i>Conclusion:</i></b> Transfusion of uncrossmatched ABO-compatible RBCs against alloantibodies is highly safe in patients with life-threatening hemorrhage.