Introduction: Early Emergency Department (ED) identification of septic patients at risk of subsequent deterioration is necessary in order to optimize disposition. High-risk patients admitted directly from the ED to the ICU have better outcomes than those admitted to the floor first. Initial ED serum lactate level has been associated with 28-day mortality in admitted patients, but there is little evidence on its use in predicting short-term deterioration. Furthermore, it is unclear whether the addition of respiratory rate (RR) to lactate would create a stronger predictive model of deterioration than either alone. Methods: Prospective cohort study of ED patients (age ≥18) screened and treated for sepsis (defined as physician suspicion of infection and 2 or more of the SIRS criteria). Lactate and vital signs were obtained within 2 hours of ED arrival. Main outcome was deterioration (defined as any of the following: death; ICU admission >24 hours; Intubation; Vasoactive medications for >1 hour; or Non-invasive positive pressure ventilation for >1 hour) within 72 hours. Patients meeting an endpoint within 1 hour of arrival were excluded. Discharged patients were contacted at 72 hours to ensure that they had not met the endpoint or presented to another institution. Results: 985 patients presenting to either of two urban high-volume EDs were enrolled, of whom 84 (8.5%) met the primary outcome. Initial serum lactate ≥ 4.0 had a specificity of 97.4% (95% CI, 94.1-100%), but a sensitivity of 27.4% (95% CI, 17-8-36.9%) for predicting deterioration. Of patients with a lactate ≥ 4.0, 4 (8.7%) were discharged home, and did not reach an endpoint at 72 hours. Lactate <2.0 had a sensitivity of 95.5% (95% CI: 93.4-97.1%) and specificity of 84.5% (95% CI: 80.4-88.6%) for ruling out 72-hour deterioration. Of patients with a lactate <2.0, 224 (56.1%) were discharged home. Combining lactate with RR (AUC: 0.72, 95% CI: 0.66-0.79) did not yield better predictive capability than lactate alone (AUC: 0.70, 95% CI: 0.64-0.76). Conclusion: Initial ED lactate is predictive of deterioration within 72 hours in patients with sepsis. The combination of lactate and RR was not more predictive of deterioration than lactate alone. This suggests that serum lactate has a role in predicting deterioration in patients with sepsis, and has utility in determining disposition.