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Background: Early detection of pediatric severe sepsis is necessary in order to optimize effective treatment, and new methods are needed to facilitate this early detection.Objective: Can a machine-learning based prediction algorithm using electronic healthcare record (EHR) data predict severe sepsis onset in pediatric populations?Methods: EHR data were collected from a retrospective set of de-identified pediatric inpatient and emergency encounters for patients between 2–17 years of age, drawn from the University of California San Francisco (UCSF) Medical Center, with encounter dates between June 2011 and March 2016.Results: Pediatric patients (n = 9,486) were identified and 101 (1.06%) were labeled with severe sepsis following the pediatric severe sepsis definition of Goldstein et al. (1). In 4-fold cross-validation evaluations, the machine learning algorithm achieved an AUROC of 0.916 for discrimination between severe sepsis and control pediatric patients at the time of onset and AUROC of 0.718 at 4 h before onset. The prediction algorithm significantly outperformed the Pediatric Logistic Organ Dysfunction score (PELOD-2) (p < 0.05) and pediatric Systemic Inflammatory Response Syndrome (SIRS) (p < 0.05) in the prediction of severe sepsis 4 h before onset using cross-validation and pairwise t-tests.Conclusion: This machine learning algorithm has the potential to deliver high-performance severe sepsis detection and prediction through automated monitoring of EHR data for pediatric inpatients, which may enable earlier sepsis recognition and treatment initiation.