Sepsis is a major public healthcare problem. It remains a significant cause of morbidity and mortality in intensive care units (ICU) all over the world. A lifesaving early specific diagnosis and treatment is a challenge as no gold standard technique exists that can alone allow a rapid and reliable diagnosis of sepsis. Histidine-rich glycoprotein (HRG) is a promising new biomarker of sepsis that can contribute to enhance current sepsis diagnostic tools. The current study aimed to evaluate HRG as a diagnostic biomarker for sepsis compared to the conventionally used biomarkers, procalcitonin (PCT) and C-reactive protein (CRP). The study included 67 participants classified into 3 groups: Control (n=19), systemic inflammatory response syndrome (SIRS) patients (n=24) and sepsis patients (n=24). Serum HRG, CRP and PCT levels were measured by ELISA techniques. HRG level was significantly reduced in sepsis patients compared with SIRS patients (P < 0.001) and controls (P < 0.001) with overall statistically significant differences between the three groups (P < 0.001). Serum levels of the 3 biomarkers revealed increased PCT level in SIRS and sepsis groups, (P=0.002 and p < 0.001 respectively), CRP level significantly increased in sepsis (P < 0.001) but not in SIRS patients (P=0.525). The area under the curve (AUC) value was 0.988 for HRG, 0.966 for PCT and 0.859 for CRP respectively. The sensitivity, specificity, PPV and NPV for diagnosis of HRG were 95.8%, 93%, 88.5%, and 97.6%, respectively. In conclusion, HRG could be a good indicator for sepsis, that can discriminate sepsis and SIRS patients in ICU.