Gastroesophageal reflux disease (GERD) is a prevalent clinical condition, that affects millions of individuals worldwide. Objective: To assess the level of soluble HLA-E (sHLA-E) as a biomarker in the diagnosis and immunopathogenesis of GERD patients. Methods: The case-control prospective study included 40 GERD patients who were consulted at the Gastroenterology Unit of AlKindy Teaching Hospital, as along with 40 healthy control subjects. The study period extended from January 2023 to May 2024. Blood was drawn from both groups and serum was separated to assesssHLA-E using a sandwich enzyme-linked immunosorbent assay (ELISA) kit. Results: There was a statistically significant difference in sHLA-E levels between GERD patients and healthy controls (P=0.021). The median sHLA-E level was significantly higher in GERD patients (0.370 ng/mL) compared to controls (0.148 ng/mL). A receiver operating characteristic (ROC) curve was generated to evaluate the diagnostic performance of soluble HLA-E (sHLA-E) in predicting GERD. The area under the ROC curve (AUC) was calculated to assess the discriminatory ability of sHLA-E with a vlue of 0.649 (95% CI: 0.534-0.752, p = 0.021). The optimal cutoff value for sHLA-E was determined to be ≤0.65 ng/mL, with a sensitivity of ‎‎85.1%, specificity of 27.3%, positive predictive value of 65.9%, negative predictive value of ‎‎69.4%, and accuracy of 35.0%.‎ Conclusion: The study provides evidence of an association between elevated sHLA-E levels and GERD. It also suggests that sHLA-E has a moderate discriminatory ability as a biomarker in predicting GERD. © 2025, Shiraz University of Medical Sciences. All rights reserved.