INTRODUCTION: The gold standard for the objective diagnosis of gastroesophageal reflux disease (GERD) is ambulatory-pH monitoring off medications. Increasingly, impedance-pH (MII-pH) monitoring on medications is being used to evaluate refractory symptoms. The aim of this study was to determine whether an MII-pH test on medications can reliably detect the presence of GERD. METHODS: Patients referred for persistent reflux symptoms despite pH confirmed adequate acid suppression (DeMeester score ≤14.7) were reviewed retrospectively. All patients who originally had MII-pH testing on medications were re-evaluated with an off medication Bravo-pH study. Acid exposure results (defined by off medication Bravo) were compared to the original on medication MII-pH. RESULTS: There were 49 patients who met study criteria (median age 51). Patients had normal acid exposure during their MII-pH test on medications (average DMS 4.35). Impedance was abnormal (normal ≤47) in 25 of the 49 patients (51%). On subsequent Bravo-pH off medications, 37 patients (75.7%) showed increased esophageal acid exposure (average DMS 36.4). Bravo-pH testing was abnormal in 84% of patients with abnormal MII testing and in 67% with normal MII testing. The sensitivity and specificity of an abnormal MII-pH on medications for increased esophageal acid exposure off medications was 56.8 and 66.7%, respectively. The positive predictive value of confirming GERD from an abnormal MII-pH on medications is 84%, while the negative predictive value is 33.3%. A receiver operating characteristic (ROC) curve was generated and the area under the curve was 0.71, indicating that MII-pH on medications is a fair test (0.7-0.8) in diagnosing pathologic GERD. CONCLUSION: Compared to the gold standard, MII-pH on medications does not reliably confirm the presence of GERD. Excellent outcomes with antireflux surgery are dependent on the presence of GERD; thus, patients should not be offered antireflux surgery until GERD is confirmed with pH testing off medications.