Background : Gastroesophageal reflux disease (GERD) is one of chronic gastrointestinal diseases in which patient may be asymptomatic or was complained from heartburn and regurgitation or pulmonary symptoms. Aim of the study : Examine the serum level of sHLA-G in GERD patients and can be used as a biomarker for early detection of GERD disease. Materials and methods : The design of the study was a case- control prospective enrolled forty patients consulted Gastroenterology Unit- Al-Kindy Teaching Hospital, were diagnosed as GERD by their physician, and compared to second forty control healthy group form January-2023 to May-2024. Serum used for quantitative assessment of soluble HLA-G (sHLA-G) using a sandwich enzyme-linked immunosorbent assay. Results : A higher proportion of females were observed in the GERD group compared to the control group (72.5% vs. 42.6%). This difference was statistically significant (p = 0.006). Level of sHLA-G Levels, a statistically non-significant difference was observed in sHLA-G levels between GERD patients and healthy controls (p = 0.158). The median sHLA-G level was non significantly higher in GERD patients (0.529 ng/mL) compared to controls (0.523 ng/mL). Conclusions : The present study provides early evidence for an association between elevated sHLA-G levels and GERD with limited diagnostic value, and revealed a significant negative correlation between sHLA-G levels and gender. Further studies is needed to elucidate the specific mechanisms underlying this relationship and to explore the potential of sHLA-G as a diagnostic or therapeutic target for GERD.