Background: Sepsis is a leading cause of morbidity and mortality that has a global burden. Early recognition of sepsis and differentiating it from similar conditions is crucial. Objective: In the present study we aimed to measure the serum level of decoy receptor 3 (DcR3) in sepsis patients to study its role as a promising biomarker for bacterial sepsis. Methodology: The present study included 30 patients, divided into a sepsis group (n=15) and a systemic inflammatory response syndrome (SIRS) group (n=15), and 15 healthy controls. Sepsis patients were identified by positive blood culture or positive 16S ribosomal DNA (rDNA) polymerase chain reaction (PCR) results. SIRS patients were identified by negative blood culture or negative 16S rDNA PCR results. Serum DcR3 level was measured by quantitative enzyme-linked immunosorbent assay (ELISA). Receiver-operating characteristic (ROC) curve analysis was performed for DcR3 and C-reactive protein (CRP) alone and in combination. Results: The serum DcR3 level was significantly higher in sepsis than SIRS patients and healthy controls (5.21 ± 2.28 ng/mL, 1.96 ± 0.90 ng/mL, and 0.95 ± 0.79 ng/mL, respectively). The ROC area under the curve (AUC) of DcR3 for sepsis versus SIRS was 0.920 at a cut-off >2.4 ng/mL, with 93.33% sensitivity and 86.67% specificity. The AUC of combined positive DcR3 and positive CRP for sepsis versus SIRS was 0.967 with 93.33% sensitivity and 100% specificity. Conclusion: DcR3, alone or in combination with CRP, is a promising biomarker for distinguishing sepsis from SIRS patients and may efficiently guide physicians to identifying sepsis patients, for whom the further usage of new diagnostics can be cost-effective.