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Purpose The purpose was to identify risk factors associated with in-hospital mortality among emergency department (ED) patients with severe sepsis and septic shock managed with early protocolized resuscitation. Methods This was a retrospective, observational cohort study in an academic, tertiary care ED. We enrolled 411 adult patients with severe sepsis and lactate ≥ 4.0 mmol/L (n = 203) or septic shock (n = 208) who received protocolized resuscitation from 2005 to 2009. Emergency department variables, microbial cultures, and in-hospital outcomes were obtained from the medical record. Multivariable regression was used to identify factors independently associated with in-hospital mortality. Results Mean age was 59.5 ± 16.3 years; 57% were male. Mean lactate was 4.8 mmol/L (3.5-6.7), 54% had positive cultures, and 27% received vasopressors in the ED. One hundred and five (26%) patients died in-hospital. Age, active cancer, do-not-resuscitate status on ED arrival, lack of fever, hypoglycemia, and intubation were independently associated with increased in-hospital mortality. Lactate clearance and diabetes were associated with a decreased risk of in-hospital death. Conclusions We identified a number of factors that were associated with in-hospital mortality among ED patients with severe sepsis or septic shock despite treatment with early protocolized resuscitation. These findings provide insights into aspects of early sepsis care that can be targets for future intervention.