Background/Aims: To date, there is no standard tool to diagnose gastroesophageal reflux disease (GERD). Typically, GERD is a non-erosive reflux disease (NERD) that does not present endoscopic abnormalities. Confocal laser endomicroscopy (CLE) has been shown to be an effective tool to identify and diagnose GERD. We aimed to investigate the cellular and vascular changes in vivo and ex vivo through CLE in patients with GERD. Methods: Patients with refractory GERD who underwent mucosectomy were recruited. The distal esophagus was observed in vivo using CLE. Mucosectomy tissue was stained with acriflavine and CLE image was obtained ex vivo. We compared cellular and vascular changes in CLE between erosive reflux disease (ERD), NERD, and a control group. Results: Eleven patients who underwent anti-reflux mucosectomy and five control patients were enrolled in the study. Patients with ERD and NERD presented greater dilated intercellular space than patients in the control group on CLE image. The diameter, number, and cross-sectional area of the intra-papillary capillary loops (IPCLs) were significantly larger in the ERD group than in the NERD group. The irregular shape of the IPCLs were observed in both patients with ERD and NERD. Conclusions The irregular shape of the IPCLs were significantly correlated with a positive diagnosis of GERD. CLE may diagnose NERD with high sensitivity and accuracy.