Purpose: In the U.S., up to 60% of patients suffer with GERD. Unfortunately, the “gold standard” for the diagnosis of gastroesophageal reflux disease (GERD) is still lacking, and the sensitivity of 24-hour pH monitoring for diagnosing NERD is unsatisfactory. Recent technological advances make the evaluation of the integrity of esophageal mucosa possible. Previous studies using confocal endoscope have demonstrated esophageal mucosal breaks and interpappilary loops (IPCLs) in patients with gastroesophageal reflux disease. pCLE is a newly developed endoscopic technique that allows the observation of living cells, tissue as well as vascular networks of the mucosal layer in the gastrointestinal tract during ongoing endoscopy. The highly magnified images (1 micron resolution) of the gastrointestinal tract mucosa can permit real-time histological analysis of the site during endoscopy. Therefore, pCLE can provide precise assessment of the esophageal squamous epithelial cells and IPCLs without the need of biopsy. We investigated the use of pCLE for in vivo evaluation of the micro alterations of the esophagus not observed by standard endoscopy in patients with NERD. Methods: A total of 19 patients with long standing reflux undergoing standard high definition upper endoscopy to evaluate for esophagitis. Eleven patients were diagnosed with NERD by the absence of endoscopic mucosal breaks. At the time of endoscopy 2.5 cc of 10% fluorescein was injected. The confocal probe was placed and optical biopsies obtained within 2 cm above the gastroesophageal junction (GEJ). Histologic specimens were also randomly obtained within 2 cm of GEJ. Transmission Electron Microscopy was performed in seven patients. The endomicroscopy images were interpreted by two experienced endoscopists. Results: See Table 1- Demographics, Table 2-Endomicroscopic Findings.Table. DemographicsConclusion: This is the first pilot study examining the utility of probe based confocal endomicrosocpy in the setting of NERD. The intercellular spaces and IPCL size were found to be largest in esophagitis group. They are also larger in NERD patients in comparison to the normal patients. pCLE could potentially provide an in vivo diagnosis via “optical biopsy.” It may be useful for evaluating microalterations of the esophagus in real time and assist the diagnosis of NERD. It could also be used as a marker to demonstrate therapeutic response for tissue healing in NERD patient and define the abnormalities at the microscopic level during endoscopy in pH negative and proton pump inhibitor unresponsive patients. Further prospective study with a larger cohort is warranted.Table: Table. Endomicroscopic Findings