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Background and Objectives: Australian Red Cross Lifeblood (Lifeblood) performs red blood cell (RBC) antibody screening on every whole blood donation. An alternate strategy has been proposed whereby an antibody screen is performed on the first donation and only repeated following pregnancy, transfusion or a significant break between donations (>2 years). We assess the blood safety risks associated with removing antibody screening for every whole blood donation. Materials and Methods: A retrospective desktop analysis included all whole blood donations collected by Lifeblood between 01 May 2018 and 30 April 2019 to quantify the antibodies that would have been undetected with the alternate strategy. The strategy was further assessed using the Alliance of Blood Operators Risk‐Based Decision‐Making framework. Results: One hundred and seventy‐one routine donors had antibodies for the first time, but reported no sensitizing event since their last donation. Forty‐seven of these had antibodies of a clinically significant specificity and titre that have the potential to cause a haemolytic transfusion reaction (HTR). The calculated risk of undetected antibodies being transfused to an incompatible recipient is 1 in 82,200. Conclusion: The estimated risk of HTRs with the alternate strategy results in an increased risk. While the alternate strategy is identified as the most cost‐effective option within the Australian setting, this additional residual risk was not deemed to be acceptable. Blood services would need to determine whether the increase in residual risk stemming from implementation of such a strategy is tolerable. [ABSTRACT FROM AUTHOR]