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Abstract Background Esophagogastroduodenoscopy is very useful in diagnosing and treating upper gastrointestinal mucosal disorders, but too much foam and water in stomach decrease its diagnostic efficiency. Simethicone administration can help remove excessive foam. Aims To determine the optimal simethicone administration strategies in a comparative randomized controlled clinical trial. Methods Adult outpatients with indications for esophagogastroduodenoscopy were enrolled and randomly divided into group 1 (simethicone solution intake 20–30 min before procedure, n = 110), group 2 (simethicone solution intake 31–60 min before procedure, n = 92), and group 3 (simethicone solution intake > 60 min before procedure). Primary and secondary outcomes were procedure time and the patients’ satisfaction after the examination. All symptoms like abdominal pain and distension were recorded. Results No statistically significant differences were found on the patients’ demographic and clinical features and mean examination time (all P values > 0.05). The distribution of patients with different endoscopic and pathological diagnosis was comparable among three groups, respectively (P = 0.607; P = 0.289). However, the proportion of patients with Gastric Cleanness Grade A was most in group 2 (n = 73, 79.3%), and patient proportion with Gastric Cleanness Grade C was most found in group 1 (n = 72, 65.5%), which was greatly different (P < 0.001). There was no statistically significant difference on the satisfaction scores [immediately 6 (3–8) vs. 6 (1–10) vs. 6 (1-9), P = 0.533; 2 h after 10 (8–10) vs. 10 (10–10) vs. 10 (8-10), P = 0.463]. Conclusion Simethicone solution intake 31–60 min before esophagogastroduodenoscopy can help obtain the best gastric cleanness, which is recommended in clinical practice (registered at ClinicalTrials.gov, NCT03776916 on December 13, 2018).