We sought to determine (a) if early lactate clearance is associated with improved survival in emergency department patients with severe sepsis and (b) the concordance between central venous oxygen saturation (ScvO2) optimization and lactate clearance during early sepsis resuscitation. Within a multicenter shock research network that uses quantitative resuscitation for severe sepsis, we analyzed prospectively collected registries of consecutive emergency department patients diagnosed with severe sepsis at three urban hospitals. Inclusion criteria are as follows: (a) age older than 17 years, (b) two or more systemic inflammation criteria, (c) systolic blood pressure 90 mmHg or less after fluid challenge or initial lactate of 4mmol/L or greater, and (d) initial and repeat lactate measurement within 6 h of resuscitation initiation. We stratified patients into two groups defined a priori based on previously published data: (a) lactate clearance-repeat lactate decrease by 10% or greater from initial (or both initial and repeat levels ≤2.0 mmol/L), and (b) lactate non-clearance-repeat lactate decrease by less than 10% from initial. The primary outcome was in-hospital mortality. Among 166 patients, lactate non-clearance occurred in 15 (9%) of 166. Mortality was 60% for lactate non-clearance versus 19% for lactate clearance, P < 0.001. On multivariate analysis, lactate non-clearance was an independent predictor of death (odds ratio, 4.9 [confidence interval, 1.5-15.9]). We found discordance between ScvO2 optimization and lactate clearance; 79% of lactate non-clearance had concomitant ScvO2 of 70% or greater. In this multicenter cohort of sepsis patients, failing to clear lactate during resuscitation carried a high risk of death, and ScvO2 optimization did not reliably exclude lactate non-clearance. These data provide rationale for a clinical trial of lactate clearance as a distinct end point of early sepsis resuscitation.