Background <p>Polyethylene glycol (PEG) is the standard agent for bowel preparation in colonoscopy. However, its combination with linaclotide may enhance bowel cleansing.</p> Aims <p>This systematic review and meta-analysis compared the efficacy and safety of linaclotide combined with PEG versus PEG alone in patients undergoing colonoscopy.</p> Methods <p>We searched PubMed, Embase, and Cochrane Library databases. We calculated pooled risk ratios (RRs) for dichotomous and mean differences (MDs) for continuous outcomes, with 95% confidence intervals (CIs).</p> Results <p>We included 8 RCTs (3591 patients). Linaclotide improved preparation quality (MD 0.31; 95% CI [0.08, 0.54]), willingness to repeat the preparation (RR 1.16; 95% CI [1.09, 1.23]), and reduced adverse events (AEs). Adenoma detection rate (ADR), polyp detection rate (PDR), cecal intubation rate, and withdrawal time were similar between the groups. Subgroup analyses showed consistent results, except for: (1) patients with constipation – linaclotide improved PDR and reduced withdrawal time; (2) studies using a lower volume of PEG in the intervention group – preparation quality was similar between groups; and (3) studies using the same volume of PEG in both groups– linaclotide improved PDR and ADR, but with similar willingness to repeat the preparation and risk of AEs.</p> Conclusion <p>Linaclotide with PEG improved preparation quality, willingness to repeat the preparation, and reduced AEs compared to PEG alone. Subgroup analyses findings are particularly relevant for patients with a history of inadequate bowel preparation, especially those with low tolerance to high-volume PEG or difficulty achieving effective colonic cleansing. Future studies should further explore the cost-effectiveness and the applicability across diverse regimens and patient characteristics.</p> Graphical abstract <p></p>