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Abstract: Background: Early, accurate determination of disease severity in an emergency setting is paramount for improving patient outcomes and healthcare costs. Monocyte anisocytosis, quantified as monocyte distribution width (MDW), has been shown to correspond with immune dysregulation. We hypothesize that MDW is broadly associated with illness severity related to sepsis and serious infection in children. Methods: We designed a retrospective study to analyze MDW, as measured by UniCel DxH 900 analyzer, on whole blood samples that were collected from children presenting for medical care between April 2020 and September 2022. SIRS criteria and Pediatric Sequential Organ Failure Assessment (pSOFA) scores were calculated, and source of infection was documented. Outcomes were compared by t test or ANOVA, and receiver operating characteristic (ROC) curves assessed accuracy of MDW in identifying sepsis in children. Results: We analyzed samples from 394 children presenting with illness to two pediatric medical centers. MDW was significantly higher in children with sepsis (28.2 ± 7.8) than children with suspected or confirmed infection who did not display signs of sepsis (21.5 ± 5.2). An ROC curve comparing MDW of children with sepsis against infected children without sepsis displayed an area under the curve of 0.78, suggesting MDW may serve as a useful tool in identifying children with sepsis. Discussion: When children present to the urgent care/emergency setting with signs of infection, MDW may serve as a prompt tool to aid clinicians in identifying those who are at high risk for severe illness and require closer monitoring/intervention compared to those who may be safely discharged home., (Copyright © 2024 by the Shock Society.)