The plasma level of soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) has been shown to be helpful in identifying critically ill patients with infection. However, it remains unknown whether it can be used to predict prognosis in patients with severe sepsis. This study investigated whether various inflammatory mediators, including sTREM-1, could be used as reliable markers to predict the prognosis of patients receiving early goal-directed therapy (EGDT). We prospectively enrolled patients 18 years or older with severe sepsis from April 2009 to May 2010 at a 2,000-bed university hospital. Patients were eligible if the initial resuscitation according to EGDT protocol was immediately performed at the emergency department. Plasma sTREM-1, C-reactive protein, and procalcitonin concentrations were measured on days 0, 3, 7, and 14. Soluble TREM-1 concentrations were significantly higher at admission and pre-EGDT in nonsurvivors (n = 16) than in survivors (n = 47) (514.1 pg/mL [interquartile range, 412.7-1,749.5 pg/mL] vs. 182.4 pg/mL [interquartile range, 54.3-327.0 pg/mL]; P = 0.001). Procalcitonin and C-reactive protein levels did not significantly differ, whereas central venous oxygen saturation and lactate levels at admission were significantly different between the two groups. The only sTREM-1 level remained significantly higher in nonsurvivors until death. On multivariate regression analysis, log(sTREM-1) (P = 0.028), central venous oxygen saturation (P = 0.022), and Simplified Acute Physiology Score II (P = 0.048) values at admission were independently significant. These results suggest that plasma sTREM-1 level at admission could be used as a marker to identify patients with a poor prognosis despite complete initial resuscitation in severe sepsis.