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The aim of this study was to validate the association between number of organ dysfunctions and mortality in emergency department (ED) patients with suspected infection.This study was conducted at two medical care center EDs. The internal validation set was a prospective cohort study conducted in Boston, USA. The external validation set was a retrospective case–control study conducted in Aarhus, Denmark. The study included adult patients (>18 years) with clinically suspected infection. Laboratory results and clinical data were used to assess organ dysfunctions. Inhospital mortality was the outcome measure. Multivariate logistic regression was used to determine the independent mortality odds for number and types of organ dysfunctions.We enrolled 4952 (internal) and 483 (external) patients. The mortality rate significantly increased with increasing number of organ dysfunctions: internal validation: 0 organ dysfunctions: 0.5% mortality, 1: 3.6%, 2: 9.5%, 3: 17%, and 4 or more: 37%; external validation: 2.2, 6.7, 17, 41, and 57% mortality (both P<0.001 for trend). Age-adjusted and comorbidity-adjusted number of organ dysfunctions remained an independent predictor. The effect of specific types of organ dysfunction on mortality was most pronounced for hematologic [odds ratio (OR) 3.3 (95% confidence interval (CI) 2.0–5.4)], metabolic [OR 3.3 (95% CI 2.4–4.6); internal validation], and cardiovascular dysfunctions [OR 14 (95% CI 3.7–50); external validation].The number of organ dysfunctions predicts sepsis mortality.