Background: Optical Enhancement technology (OE) combines bandwidth-limited light and image enhancement processing technology to enhance subtle mucosal and vascular details. This is the first study assessing the new technology for the diagnosis of gastroesophageal reflux disease (GERD). Patients and Methods: Consecutive patients with GERD and controls were prospectively included. The distal esophagus was examined in all quadrants with high definition white-light endoscopy (HD-WLE) followed by OE and biopsies for histopathological analysis. Features observed only by OE were compared between controls and patients with GERD. Results: A total of 100 areas were evaluated. About 56% of patients had a diagnosis of GERD. The mean age of patients was 53 years (range 27–89 years), 60% were female. Compared to controls, patients with diagnosis of GERD showed significantly more often tortuosity (p = 0.042), dilation (p = 0.0003), and increased number (p = 0.001) of intrapapillary capillary loops (IPCLs). In addition, increased vascularity and mucosal breaks were significantly more often found in patients with GERD as compared to controls (p < 0.05). On multivariate analysis, increased number and dilation of IPCL were the best predictors of GERD. Conclusions: The newly introduced OE technology significantly improves the diagnosis of GERD compared to HD-WLE. The results should be confirmed in a multicenter trial.