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To prospectively and externally validate the Mortality in Emergency Department Sepsis (MEDS) score as a predictor of 28-day mortality in patients who present to the emergency department with a systemic inflammatory response syndrome.Multicentered prospective cohort study.Emergency departments at the University of Colorado Hospital and Denver Health Medical Center in Denver, CO, and Albert Einstein Medical Center and the Hospital of the University of Pennsylvania in Philadelphia, PA.Adult patients who presented to the emergency department, who met criteria for systemic inflammatory response syndrome, and who were admitted to the hospital.The MEDS score was calculated by recording the presence of terminal illness, tachypnea or hypoxemia, septic shock, platelet count <150,000 cells/mm3, band count as a percentage of total white blood cell count >5%, age >65 yrs, lower respiratory infection, nursing home residence, and altered mental status.Mortality within 28 days or discharged alive from the hospital.In all, 385 patients were enrolled between 18 and 100 yrs of age. The overall mortality was 9%. As in the original article, the MEDS score was categorized into five groups: very low, low, moderate, high, and very high for 28-day mortality. Mortality rates for each group were 0.6% (95% confidence interval [CI], 0%–3%), 5% (95% CI, 1%-13%), 19% (95% CI, 11%-29%), 32% (95% CI, 15%-54%), and 40% (95% CI, 12%-74%), respectively. The MEDS score had an area under the receiver operating characteristic curve of 0.88 (95% CI, 0.83-0.92).The MEDS score accurately predicts 28-day mortality in patients who present to the emergency department with systemic inflammatory response syndrome and who are admitted to the hospital.