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Aim: To investigate the efficacy of premedication with pronase, a proteolytic enzyme, in improving image quality during magnifying endoscopy., Methods: The study was of a blinded, randomized, prospective design. Patients were assigned to groups administered oral premedication of either pronase and simethicone (Group A) or simethicone alone (Group B). First, the gastric mucosal visibility grade (1-4) was determined during conventional endoscopy, and then a magnifying endoscopic examination was conducted. The quality of images obtained by magnifying endoscopy at the stomach and the esophagus was scored from 1 to 3, with a lower score indicating better visibility. The endoscopist used water flushes as needed to obtain satisfactory magnifying endoscopic views. The main study outcomes were the visibility scores during magnifying endoscopy and the number of water flushes., Results: A total of 144 patients were enrolled, and data from 143 patients (M:F=90:53, mean age 57.5 years) were analyzed. The visibility score was significantly higher in the stomach following premedication with pronase (73% with a score of 1 in Group A vs 49% in Group B, P<0.05), but there was no difference in the esophagus visibility scores (67% with a score of 1 in Group A vs 58% in Group B). Fewer water flushes [mean 0.7±0.9 times (range: 0-3 times) in Group A vs 1.9±1.5 times (range: 0-6 times) in Group B, P<0.05] in the pronase premedication group did not affect the endoscopic procedure times [mean 766 s (range: 647-866 s) for Group A vs 760 s (range: 678-854 s) for Group B, P=0.88]. The total gastric mucosal visibility score was also lower in Group A (4.9±1.5 vs 8.3±1.8 in Group B, P<0.01)., Conclusion: The addition of pronase to simethicone premedication resulted in clearer images during magnifying endoscopy and reduced the need for water flushes.