The predisposition, infection/insult, response and organ dysfunction (PIRO) staging system for septic patients allows grouping of heterogeneous patients into homogeneous subgroups.The purposes of this single-center, prospective, observational cohort study were to create a PIRO system for patients with community-acquired sepsis (CAS) presenting to the emergency department (ED) and assess its prognostic and stratification capabilities.Septic patients were enrolled and allocated to derivation (n =831) or validation (n =860) cohorts according to their enrollment dates.The derivation cohort was used to identify independent predictors of mortality and create a PIRO system by binary logistic regression analysis, and the prognostic performance of PIRO was investigated in the validation cohort by receiver operator characteristic (ROC) curve.Ten independent predictors of 28-day mortality were identified.The PIRO system combined the components of predisposition (age, chronic obstructive pulmonary disease, hypoalbumninemia), infection (central nervous system infection), response (temperature, procalcitonin) and organ dysfunction (brain natriuretic peptide, troponin I, mean arterial pressure, Glasgow coma scale score).The area under the ROC of PIRO was 0.833 for the derivation cohort and 0.813 for the validation cohort.There was a stepwise increase in 28-day mortality with increasing PIRO score and the differences between the low-(PIRO 0-10), intermediate-(11-20) and high-(>20) risk groups were very significant in both cohorts (p < 0.01).The present study demonstrates that this PIRO system is valuable for prognosis and risk stratification in patients with CAS in the ED.