Objectives: The National Early Warning Score (NEWS) helps to estimate mortality risk in emergency department (ED) patients. This study aimed to investigate whether the prognostic value of the NEWS at ED admission could be further improved by adding inflammatory blood markers (i.e. white blood cell count (WBC), procalcitonin (PCT), and MR-ProAdrenomedullin (MR-proADM). Design: Secondary analysis of a multinational, observational study. (TRIAGE study, March 2013 to October 2014) Setting: Three tertiary care centers in France, Switzerland, and the USA. Participants: A total of 1303 adult medical patients with complete NEWS data seeking ED care were included in the final analysis. NEWS was calculated retrospectively based on admission data. Main outcome measures: The primary outcome was all-cause 30-day mortality. Secondary outcome was ICU admission. We used multivariate regression analyses to investigate associations of NEWS and blood markers with outcomes and area under the receiver operating curve (AUC) as a measure of discrimination. Results: Of the 1303 included patients, 54 (4.1%) died within 30 days. The NEWS alone showed fair prognostic accuracy for all-cause 30-day mortality (AUC 0.73), with a multivariate adjusted odds ratio (OR) of 1.26 (95% CI 1.13–1.40, p<0.001). The AUCs for the prediction of mortality using the inflammatory markers WBC, PCT, and MR-proADM were 0.64, 0.71, and 0.78, respectively. Combining NEWS with all three blood markers or only with MR-proADM clearly improved discrimination with an AUC 0.82 (p= 0.002). Combining the three inflammatory markers with NEWS improved prediction of ICU admission (AUC 0.70 vs. 0.65 when using NEWS alone, p=0.006). Conclusion: NEWS is helpful in risk stratification of ED patients and can be further improved by the addition inflammatory blood markers. Future studies should investigate whether risk stratification by NEWS in addition to biomarkers improve site-of-care decision in this patient population. Trial registration number: ClinicalTrials.gov; Identifier: NCT01768494