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Objectively diagnosing non-erosive reflux disease (NERD) is still a challenge. We aimed to evaluate the use ofin-vivoconfocal laser endomicroscopy (CLE) to examine the microalterations of the esophagus in patients with NERD and its relationship with reflux episodes monitored by multiple intraluminal impedance-pH (MII-pH).Patients with gastroesophageal reflux symptoms completed reflux disease questionnaires. NERD was determined by negative gastroscopy. Patients without reflux symptoms were recruited as controls. Pilot clinical study was followed by prospective controlled blinded study. All subjects were examined by white-light mode of the endoscopy followed by the standard CLE mode and then MII-pH monitoring. The microalterations seen on CLE images and the correlation between CLE features and reflux episodes were evaluated, the correlation between CLE and transmission electron microscope (TEM) data was also analyzed.On CLE images, NERD patients had more intrapapillary capillary loops (IPCLs) per image than did controls (8.29±3.52 vs. 5.69±2.31,P=0.010), as well as the diameter of IPCLs (19.48±3.13 vs. 15.87±2.21 μm,P=0.041) and intercellular spaces of squamous cells (3.40±0.82 vs. 1.90±0.53 μm,P=0.042). The receiver operating characteristic analysis indicated that IPCLs number (optimal cutoff >6 per image, area under the curve (AUC) 0.722, 95% confidence interval (CI) 0.592–0.853, sensitivity 67.7%, specificity 71.6%), IPCLs diameter (optimal cutoff >17.2 μm, AUC 0.847, 95% CI 0.747–0.947, sensitivity 81%, specificity 76%), and the intercellular spaces of squamous cells (optimal cutoff >2.40 μm, AUC 0.935, 95% CI 0.875–0.995, sensitivity 85.7%, specificity 90.5%) diagnosed NERD with reasonable accuracy. Combined features of dilatation of intercellular space plus increased IPCLs provided 100% specificity in the diagnosis of NERD patients. The intercellular spaces of squamous cells observed on CLE were highly related to that on TEM findings (r=0.75,P<0.001). Multivariate progressive regression analysis showed that acidic reflux, especially in the supine position, was related to the increased number and dilation of IPCLs in the squamous epithelium (β=0.063,t=2.895,P=0.038 andβ=0.156,t=1.023,P=0.04).CLE represents a useful and potentially significant improvement over standard endoscopy to examine the microalterations of the esophagusin vivo. Acidic reflux is responsible for the microalterations in the esophagus of patients with NERD.