The prognostic value of procalcitonin (PCT) in patients with sepsis at the emergency department (ED) has not been evaluated. We conducted a prospective observational study to compare the prognostic value of PCT on sepsis and compared with a validated score, Mortality in Emergency Department Sepsis (MEDS) score, and C-reactive protein (CRP) in the setting of ED of an urban, university-based medical center. Five hundred twenty-five consecutive adult patients admitted to the ED fulfilling the American College of Clinical Pharmacists/Society of Critical Care Medicine Consensus Conference definition of sepsis were prospectively enrolled. Serum PCT and CRP were evaluated for each patient. Clinical characteristics and laboratory results on ED admission were recorded using a standardized form. Each patient was followed for at least 30 days. The main outcome was early (5-day) and late (6- to 30-day) mortality. The median age of the study sample was 64.0 (interquartile range, 47-76) years old, and the overall 30-day mortality rate was 10.5%. The c-statistic in the prediction of early mortality was 0.89 for MEDS, 0.76 for PCT, and 0.68 for CRP. The c-statistic in the prediction of late mortality was 0.78 for MEDS, 0.70 for PCT, and 0.63 for CRP. Overall, MEDS score has the best discriminative capability among the three tested markers. Under the best cutoff value, PCT was the most sensitive, and MEDS score was the most specific marker. We suggest further combining the information on PCT and MEDS score to enhance the accuracy in predicting ED sepsis mortality.