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To determine the use of end-tidal carbon dioxide (ETCO2) as an end point of sepsis resuscitation.This was a prospective, observational, single-center cohort study of emergency department patients receiving treatment for severe sepsis with a quantitative resuscitation protocol. Three ETCO2 readings were taken during a 1-minute time frame at 0, 3, and 6 hours of treatment. Linear regression was used to characterize the association between ETCO2 and central venous oxygen saturation (SCVO2) and lactate and also to determine the relationship between their change. Analysis of variance was used to determine the relationship between ETCO2 and disposition.Sixty-nine patients were included in our final analysis. For baseline values, linear regression failed to show a relationship between ETCO2 and SCVO2 (β = −0.04, t(70) = −0.53, P = .60) but showed a nearly significant relationship (β = −0.51, t(70) = −1.90, P = .06) with lactate. There was no significant relationship between ETCO2 and SCVO2 at 3 hours (β = 0.12, t(70) = 1.43, P = .16) or 6 hours (β = 0.05, t(64) = 0.82, P = .67). There was also no significant relationship between 6-hour change in ETCO2 and change in SCVO2 (β = 0.04, t(64) = 0.43, P = .67) or lactate (β = 0.04, t(59) = 0.52, P = .60) or disposition (F(4) = 0.78, P = .54).End-tidal carbon dioxide is unlikely to be a useful clinical end point for sepsis resuscitation, although it may be useful as a triage tool in suspected sepsis because baseline values may reflect initial lactate.