OBJECTIVEWe sought to develop Artificial Intelligence (AI) based models to predict non-transplantable recurrence (NTR) of hepatocellular carcinoma (HCC) following hepatic resection (HR).METHODSHCC patients who underwent HR between 2000-2020 were identified from a multi-institutional database. NTR was defined as recurrence beyond Milan Criteria. Different machine learning (ML) and deep learning (DL) techniques were used to develop and validate two prediction models for NTR, one using only preoperative factors and a second using both preoperative and postoperative factors.RESULTSOverall, 1763 HCC patients were included. Among 877 patients with recurrence, 364 (41.5%) patients developed NTR. An ensemble AI model demonstrated the highest area under ROC curves (AUC) of 0.751 (95% CI: 0.719-0.782) and 0.717 (95% CI:0.653-0.782) in the training and testing cohorts, respectively which improved to 0.858 (95% CI: 0.835-0.884) and 0.764 (95% CI: 0.704-0.826), respectively after incorporation of postoperative pathologic factors. Radiologic tumor burden score and pathological microvascular invasion were the most important preoperative and postoperative factors, respectively to predict NTR. Patients predicted to develop NTR had overall 1- and 5-year survival of 75.6% and 28.2%, versus 93.4% and 55.9%, respectively, among patients predicted to not develop NTR (p < 0.0001).CONCLUSIONThe AI preoperative model may help inform decision of HR versus LT for HCC, while the combined AI model can frame individualized postoperative care (https://altaf-pawlik-hcc-ntr-calculator.streamlit.app/).