Objective: The number of patients requiring prolonged mechanical ventilation (PMV) is increasing worldwide, but the weaning outcome prediction model in these patients is still lacking. We hence aimed to develop an explainable machine learning (ML) model to predict successful weaning in patients requiring PMV using a real-world dataset.Methods: This retrospective study used the electronic medical records of patients admitted to a 12-bed respiratory care center in central Taiwan between 2013 and 2018. We used three ML models, namely, extreme gradient boosting (XGBoost), random forest (RF), and logistic regression (LR), to establish the prediction model. We further illustrated the feature importance categorized by clinical domains and provided visualized interpretation by using SHapley Additive exPlanations (SHAP) as well as local interpretable model-agnostic explanations (LIME).Results: The dataset contained data of 963 patients requiring PMV, and 56.0% (539/963) of them were successfully weaned from mechanical ventilation. The XGBoost model (area under the curve [AUC]: 0.908; 95% confidence interval [CI] 0.864–0.943) and RF model (AUC: 0.888; 95% CI 0.844–0.934) outperformed the LR model (AUC: 0.762; 95% CI 0.687–0.830) in predicting successful weaning in patients requiring PMV. To give the physician an intuitive understanding of the model, we stratified the feature importance by clinical domains. The cumulative feature importance in the ventilation domain, fluid domain, physiology domain, and laboratory data domain was 0.310, 0.201, 0.265, and 0.182, respectively. We further used the SHAP plot and partial dependence plot to illustrate associations between features and the weaning outcome at the feature level. Moreover, we used LIME plots to illustrate the prediction model at the individual level. Additionally, we addressed the weekly performance of the three ML models and found that the accuracy of XGBoost/RF was ~0.7 between weeks 4 and week 7 and slightly declined to 0.6 on weeks 8 and 9.Conclusion: We used an ML approach, mainly XGBoost, SHAP plot, and LIME plot to establish an explainable weaning prediction ML model in patients requiring PMV. We believe these approaches should largely mitigate the concern of the black-box issue of artificial intelligence, and future studies are warranted for the landing of the proposed model.