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Introduction In critically ill patients, individualised strategies for red blood cell transfusion (RBCT) are lacking. The objective of this study is to demonstrate the potential advantages of employing an individualised transfusion strategy compared with a restrictive approach, in unselected intensive care unit (ICU) patients.Methods This will be a randomised, multicentre, international trial. Two open-label parallel groups will be compared with an allocation ratio of 1:1. The trial is designed to investigate the superiority of the individualised intervention group compared with the standard intervention group. The study will be performed in three mixed, academic ICUs located in two different countries. In the individualised group, prescription of RCBT is restricted to patients who present haemoglobin (Hb) ≤9.0 g/dL and oxygen extraction ratio (O2ER) ≥ 30%, for a minimum Hb value of ≤6.0 g/dL. In the control group, prescription of RBCT is guided by thresholds proposed by recent guidelines, regardless of O2ER values.Ethics and dissemination This trial is approved by the Comitato Etico Area Vasta Centro della Regione Emilia-Romagna (protocol number 350/2023/Sper/AOUFe/PRBCT, date of approval 18/05/2023) and ethic boards at all participating sites. Our results will be published and shared with relevant organisations and healthcare professionals.Trial registration number Clinicaltrials.gov NCT06102590