BACKGROUND Our aim was to determine a useful combination of blood biomarkers that can predict 28-day mortality of sepsis upon arrival at the Emergency Department (ED). MATERIAL AND METHODS Based on Sepsis-3.0, 90 sepsis patients were enrolled and divided into survivor and nonsurvivor groups with day 28 as the study end point. After comparing the demographic data and clinical characteristics of patients, we evaluated the predictive validity of a combination of markers including interleukin-6 (IL-6), procalcitonin (PCT), and lactate at arrival at the ED. Independent risk factors were found by using univariate and multivariate logistic regression analyses, and the prognostic value of markers was determined by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS There were 67 (74.4%) survivors and 23 (25.6%) nonsurvivors. The levels of IL-6 (survivors vs nonsurvivors: median 205.30 vs 3499.00 pg/mL, P=0.012) and lactate (survivors vs. nonsurvivors: median 2.37 vs 5.77 mmol/L, P=0.003) were significantly lower in survivor group compared with the nonsurvivor group. Markers including IL-6, PCT, lactate, and neutrophil-to-white blood cell ratio (NWR) were independent risk factors in predicting 28-day mortality due to sepsis. The combination of these 4 markers provided the best predictive performance for 28-day mortality of patients with sepsis, on arrival at the ED (AUC of 0.823, 95% confidence interval [CI] 0.723-0.924), and its accuracy, specificity, and sensitivity were 74.4% (95% CI 64.0-82.8%), 91% (95% CI 80.9-96.3%), and 65% (95% CI 42.8-82.8%), respectively. CONCLUSIONS The combination of IL-6, PCT, lactate, and NWR measurements is a potential predictor of 28-day mortality for patients with sepsis, at arrival at the ED. Further research is needed to confirm our findings.