Physiologic scoring systems are often used to prognosticate mortality in critically ill patients. This study examined the performance of Acute Physiology and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) II, Mortality in Emergency Department Sepsis (MEDS), and Mortality Probability Models (MPM) II0 in predicting in-hospital mortality of patients in the emergency department meeting criteria for early goal-directed therapy and the severe sepsis resuscitation bundle. The discrimination and calibration characteristics of APACHE II, SAPS II, MEDS, and MPM II0 were evaluated. Data are presented as median and quartiles (25th, 75th). Two-hundred forty-six patients aged 68 (52, 81) years were analyzed from a prospectively maintained sepsis registry, with 76.0% of patients in septic shock, 45.5% blood culture positive, and 35.0% in-hospital mortality. Acute Physiology and Chronic Health Evaluation II, SAPS II, and MEDS scores were 29 (21, 37), 54 (40, 70), and 13 (11, 16), with predicted mortalities of 64% (40%, 85%), 58% (25%, 84%), and 16% (9%, 39%), respectively. Mortality Probability Models II0 showed a predicted mortality of 60% (27%, 80%). The area under the receiver operating characteristic curves was 0.73 for APACHE II, 0.71 for SAPS II, 0.60 for MEDS, and 0.72 for MPM II0. The standardized mortality ratios were 0.59, 0.63, 1.68, and 0.64, respectively. Thus, APACHE II, SAPS II, MEDS, and MPM II0 have variable abilities to discriminate early and estimate in-hospital mortality of patients presenting to the emergency department requiring the severe sepsis resuscitation bundle. Adoption of these prognostication tools in this setting may influence therapy and resource use for these patients.