Background The tendency of sepsis to progress rapidly and the benefit of an early start of treatment emphasise the importance of fast risk stratification in the emergency department (ED). The aim of the present work was to validate the Mortality in Emergency Department Sepsis (MEDS) score as a predictor of 28-day mortality in ED patients with sepsis in The Netherlands, and to compare its performance to C reactive protein (CRP) and lactate. Methods This was a historical cohort study in a secondary and tertiary care university hospital. Patients were included if they were seen by an internist in the ED, fulfilled the clinical criteria for sepsis and were admitted to the hospital. Primary outcome was all-cause in-hospital mortality within 28 days. Results In the 6-month study period, 331 patients were included, of whom 38 (11.5%) died. Mortality varied significantly per MEDS category: ≤4 points (very low risk: 3.1%), 5–7 points (low risk: 5.3%), 8–12 points (moderate risk 17.3%), 13–15 points (high risk: 40.0%), >15 points (very high risk: 77.8%). Receiver operating characteristic (ROC) analysis showed that the MEDS score predicted 28-day mortality better than CRP (area under the curve (AUC) values of 0.81 (95% CI 0.73 to 0.88) and 0.68 (95% CI 0.58 to 0.78), respectively). Lactate was not measured in enough patients (47) for a valid evaluation, but seemed to predict mortality at least fairly (AUC 0.75, 95% CI 0.60 to 0.90). Conclusions The MEDS score is an adequate tool for predicting mortality in patients with sepsis in a Dutch internistic ED population. CRP is less useful in this context. Lactate appears to be at least a fair predictor of mortality, but needs to be investigated more systematically in a larger population.