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Postoperative sepsis is one of the main causes of mortality after liver transplantation (LT). Our study aimed to develop and validate a predictive model for postoperative sepsis within 7 d in LT recipients using machine learning (ML) technology. Data of 786 patients received LT from January 2015 to January 2020 was retrospectively extracted from the big data platform of Third Affiliated Hospital of Sun Yat-sen University. Seven ML models were developed to predict postoperative sepsis. The area under the receiver-operating curve (AUC), sensitivity, specificity, accuracy, and f1-score were evaluated as the model performances. The model with the best performance was validated in an independent dataset involving 118 adult LT cases from February 2020 to April 2021. The postoperative sepsis-associated outcomes were also explored in the study. After excluding 109 patients according to the exclusion criteria, 677 patients underwent LT were finally included in the analysis. Among them, 216 (31.9%) were diagnosed with sepsis after LT, which were related to more perioperative complications, increased postoperative hospital stay and mortality after LT (all p < .05). Our results revealed that a larger volume of red blood cell infusion, ascitic removal, blood loss and gastric drainage, less volume of crystalloid infusion and urine, longer anesthesia time, higher level of preoperative TBIL were the top 8 important variables contributing to the prediction of post-LT sepsis. The Random Forest Classifier (RF) model showed the best overall performance to predict sepsis after LT among the seven ML models developed in the study, with an AUC of 0.731, an accuracy of 71.6%, the sensitivity of 62.1%, and specificity of 76.1% in the internal validation set, and a comparable AUC of 0.755 in the external validation set. Our study enrolled eight pre- and intra-operative variables to develop an RF-based predictive model of post-LT sepsis to assist clinical decision-making procedure. Postoperative sepsis is one of the main causes of mortality after liver transplantation (LT).Our results revealed that a larger volume of red blood cell infusion, ascitic removal, blood loss and gastric drainage, less volume of crystalloid infusion and urine, longer anesthesia time, higher level of preoperative TBIL were the top 8 important variables contributing to the prediction of post-LT sepsis.The Random Forest Classifier (RF) model showed the best overall performance to predict sepsis after LT in our study, which could assist in the clinical decision-making procedure. Postoperative sepsis is one of the main causes of mortality after liver transplantation (LT). Our results revealed that a larger volume of red blood cell infusion, ascitic removal, blood loss and gastric drainage, less volume of crystalloid infusion and urine, longer anesthesia time, higher level of preoperative TBIL were the top 8 important variables contributing to the prediction of post-LT sepsis. The Random Forest Classifier (RF) model showed the best overall performance to predict sepsis after LT in our study, which could assist in the clinical decision-making procedure.