An accurate reflux-symptom relationship analysis method is an unmet need in gastroesophageal reflux disease (GERD) diagnosis. The aim of this study was to adapt signal detection theory (SDT) approach to reflux-symptom relationship analysis to develop a new diagnosis method. Patients with predominant symptoms of heartburn and regurgitation were enrolled. Proton pump inhibitor (PPI)-responsive and PPI-unresponsive groups were created via interview and PPI trial. Patients then underwent stationary esophageal manometry and 24-hour multichannel intraluminal impedance-pH monitoring. SDT measurement parameters (discriminability: d and criterion: c) were calculated using empirically selected time windows (0.5, 1, 2, 3, 4 and 5 minutes). The time window that provided the highest d value was selected as the optimal time window. A cut-off d value that optimally separates two groups was found using receiver operating characteristics analysis. Sixty-three patients completed the study (45 PPI responsive). Optimal time window and cut-off d value were found as 1 and 0.767 minute, respectively. Symptom association probability (SAP) index values showed good correlation (r(S) = 0.7182, P < 0.0001) with d values. SDT approach to reflux-symptom relationship analysis showed sensitivity (89% vs. 78%) and negative predictive values (75% vs. 60%) favorable over SAP index analysis. SDT approach using 1-minute time window and 0.767 cut-off d value provides us a new and more accurate measure of reflux-symptom relationship than SAP index analysis.