Background: Ventilator-associated pneumonia (VAP) is a serious infection that affects patients on ventilators in intensive care units (ICUs). Early diagnosis and treatment are crucial to improve outcomes. Researchers are looking for new biomarkers to help diagnose and manage VAP, including Histidine-rich glycoprotein (HRG) and Triggering Receptor Expressed on Myeloid cells-1 (TREM-1), which have shown promise in predicting disease severity and outcomes. This study aimed to investigate and compare the diagnostic and prognostic utility of sTREM-1 and HRG in adult ICU patients with ventilator-associated pneumonia, filling a current knowledge gap in the field. Method: A total of 90 patients intubated in ICU were enrolled in this study. Patients were divided into VAP group (n = 45), non-VAP group (n = 45). The HRG, sTREM-1, C reactive protein (CRP) and white blood cells levels were measured on admission & 72 hours after intubation. Results: The study found that patients with ventilator-associated pneumonia (VAP) have a unique and deteriorating biomarker profile over time. Compared to non-VAP patients, VAP patients had significantly lower HRG levels and higher sTREM-1 levels. Initially, VAP patients had low HRG and moderate sTREM-1 levels, but over 72 hours, HRG levels decreased further while sTREM-1 levels increased, indicating a worsening inflammatory response. Conclusion: sTREM-1 levels at 72 hours were a stronger predictor of VAP than HRG levels, monitoring HRG and sTREM-1 levels over time could help doctors diagnose ventilator-associated pneumonia (VAP) earlier, identify patients at higher risk, and tailor treatments to individual needs.