<b><i>Introduction:</i></b> Current guidelines suggest adding oral simethicone to bowel preparation for colonoscopy. However, its effect on key quality indicators for screening colonoscopy remains unclear. The primary aim was to assess the rate of adequate bowel preparation in split-dose high-volume polyethylene glycol (PEG), with or without simethicone. <b><i>Methods:</i></b> This is an endoscopist-blinded, randomized controlled trial, including patients scheduled for colonoscopy after a positive faecal immunochemical test. Patients were randomly assigned to 4 L of PEG split dose (PEG) or 4 L of PEG split dose plus 500 mg oral simethicone (PEG + simethicone). The Boston Bowel Preparation Scale (BBPS) score, the preparation quality regarding bubbles using the Colon Endoscopic Bubble Scale (CEBuS), ADR, CIR, and the intraprocedural use of simethicone were recorded. <b><i>Results:</i></b> We included 191 and 197 patients in the PEG + simethicone group and the PEG group, respectively. When comparing the PEG + simethicone group versus the PEG group, no significant differences in adequate bowel preparation rates (97% vs. 93%; <i>p</i> = 0.11) were found. However, the bubble scale score was significantly lower in the PEG + simethicone group (0 [0] versus 2 [5], <i>p</i> < 0.01), as well as intraprocedural use of simethicone (7% vs. 37%; <i>p</i> < 0.01). ADR (62% vs. 61%; <i>p</i> = 0.86) and CIR (98% vs. 96%, <i>p</i> = 0.14) did not differ between both groups. <b><i>Conclusion:</i></b> Adding oral simethicone to a split-bowel preparation resulted in a lower incidence of bubbles and a lower intraprocedural use of simethicone but no further improvement on the preparation quality or ADR.