Background <p>Acid suppression with proton pump inhibitors (PPIs) or a potassium-competitive acid blocker (P-CAB) is the first-line treatment for gastroesophageal reflux disease (GERD); however, a significant proportion of patients exhibit symptomatically refractory GERD. Here, we investigated whether distinct serum miRNA profiles exist in individuals with persistent symptoms despite acid suppression, given that serum miRNAs are promising biomarkers for cancer detection and various pathophysiological conditions. We also examined the relationship between anxiety/depression and serum miRNAs associated with symptomatic refractoriness.</p> Methods <p>GERD patients taking PPIs/P-CAB for at least 8 weeks were enrolled and were classified into symptomatically refractory and symptomatically responsive groups using a GerdQ questionnaire. Comprehensive serum miRNA profiling was performed for all participants. Logistic LASSO/Elastic Net regression analysis was used to identify miRNAs associated with symptomatic refractoriness to PPIs/P-CAB, and a discriminant model was developed. Associations of the identified miRNAs with the presence of reflux esophagitis (RE) and items on the Hospital Anxiety and Depression Scale (HADS) were assessed.</p> Results <p>A combination of four serum miRNAs (miR-4294, miR-4725-3p, miR-3679-5p, and miR-6893-5p) was able to distinguish the symptomatically refractory group from the responsive group (sensitivity, 0.83; specificity, 0.66; AUC, 0.79). This AUC was higher than that for the presence of RE. The serum levels of three of the four miRNAs were associated with items on the HADS-A subscales.</p> Conclusions <p>Distinct serum miRNA profiles are associated with symptom persistence despite acid suppression, potentially reflecting neuropsychological factors. These findings may provide new insights into the complex pathophysiology of symptomatically refractory GERD.</p>