The rapid deterioration observed in the condition of some hospitalized patients can be attributed to either disease progression or imperfect triage and level of care assignment after their admission. An early warning system (EWS) to identify patients at high risk of subsequent intrahospital death can be an effective tool for ensuring patient safety and quality of care and reducing avoidable harm and costs.The aim of this study was to prospectively validate a real-time EWS designed to predict patients at high risk of inpatient mortality during their hospital episodes.Data were collected from the system-wide electronic medical record (EMR) of two acute Berkshire Health System hospitals, comprising 54,246 inpatient admissions from January 1, 2015, to September 30, 2017, of which 2.30% (1248/54,246) resulted in intrahospital deaths. Multiple machine learning methods (linear and nonlinear) were explored and compared. The tree-based random forest method was selected to develop the predictive application for the intrahospital mortality assessment. After constructing the model, we prospectively validated the algorithms as a real-time inpatient EWS for mortality.The EWS algorithm scored patients' daily and long-term risk of inpatient mortality probability after admission and stratified them into distinct risk groups. In the prospective validation, the EWS prospectively attained a c-statistic of 0.884, where 99 encounters were captured in the highest risk group, 69% (68/99) of whom died during the episodes. It accurately predicted the possibility of death for the top 13.3% (34/255) of the patients at least 40.8 hours before death. Important clinical utilization features, together with coded diagnoses, vital signs, and laboratory test results were recognized as impactful predictors in the final EWS.In this study, we prospectively demonstrated the capability of the newly-designed EWS to monitor and alert clinicians about patients at high risk of in-hospital death in real time, thereby providing opportunities for timely interventions. This real-time EWS is able to assist clinical decision making and enable more actionable and effective individualized care for patients' better health outcomes in target medical facilities.