Background: Despite significant advances in the diagnosis and management of sepsis and trauma over the past few decades, severe infection and injury continue to represent major public health challenges. Fibrinogen-like protein 2 (FGL2), a member of the fibrinogen family, can be expressed as a membrane-associated protein with coagulation activity or in a secreted form possessing unique immune suppressive functions. In this study, we evaluated whether soluble fibrinogen-like protein 2 (sFGL2) can serve as a biomarker to predict the development of sepsis in trauma patients. Methods: sFGL2 concentrations were determined by ELISA assays in sera of 75 trauma patients clinically classified into non-sepsis group and sepsis group. For comparison, 15 age- and sex-matched healthy individuals were included. Results: sFGL2 concentrations were dramatically elevated in trauma patients compared to healthy controls. In the patient group, the patients with sepsis showed a significant increase in sFGL2 concentrations compared with non-septic patients. Moreover, non-survivors of septic patients displayed higher sFGL2 concentrations compared with survivors. In addition, sFGL2 concentrations were positively correlated with Sequential Organ Failure Assessment (SOFA) scores, serum IL-8 and IL-10 concentrations, but reversely correlated with Glasgow coma scale (GCS) scores, platelet and lymphocyte counts. Furthermore, sFGL2 was found to be an independent predictor of 28-day mortality in traumatic patients with sepsis by logistic regression analysis. Conclusion: sFGL2 concentrations were significantly correlated with the development and mortality of sepsis in traumatic patients. Thus, sFGL2 may serve as a potential indicator for traumatic patients with sepsis.