Abstract Background Iron deficiency (ID) is linked to an increased need for perioperative red blood cell (RBC) transfusion in cardiac surgery. The soluble transferrin receptor (sTfR), an inflammation-independent marker of ID, has emerged as a potential marker for evaluating iron status. However, the relationship between sTfR level and the need for a high-volume of RBC transfusion in pediatric cardiac surgery patients has not been explored. Purpose The objective of this study was to explore the distribution of sTfRs and their association with high-volume RBC transfusion in infants during cardiac surgery. Methods From August 2021 to July 2022, 236 low-weight infants (≤10 kg) who underwent cardiac surgery were included in this study. Preoperative sTfR levels and the volume of RBCs perioperatively transfused were recorded. Receiver operating characteristic curve analysis and multivariable logistic model were used to explore the association between sTfR levels and the need for a high-volume of RBC transfusion in this study. Results In our study, 29 (12.2%) patients received more than 2 units during the perioperative period. sTfR level was the most accurate marker for predicting the need for RBC transfusion (AUC=0.643, cutoff=17.53 nmol/L, sensitivity=58.6%, specificity=73.9%). Moreover, in both the continuous and categorical variable-adjusted models, a high sTfR level was associated with a greater need for RBC transfusion (P=0.006; P<0.001). Conclusions RBC transfusion is common for low-weight infants undergoing cardiac surgery. Furthermore, a high preoperative sTfR level is associated with the need for a high-volume perioperative RBC transfusion.