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Abstract Background Endoscopic mucosal resection (EMR) to remove colon polyps is increasingly common in patients taking antithrombotic agents. The safety of EMR with submucosal saline injection has not been clearly demonstrated in this population. Aims The present study aimed to evaluate the efficacy and safety of submucosal injection of saline–epinephrine versus hypertonic saline in colorectal EMR of patients taking antithrombotic agents. Methods This study enrolled 204 patients taking antithrombotic agents among 995 consecutive patients who underwent colonic EMR from April 2012 to March 2018 at Ureshino Medical Center. Patients were divided into two groups according to the injected solution: saline–epinephrine or hypertonic (10%) saline (n = 102 in each group). Treatment outcomes and adverse events were evaluated in each group and risk factors for immediate and post-EMR bleeding were investigated. Results There were no differences between groups in patient or polyp characteristics. The main antithrombotic agents were low-dose aspirin, warfarin, and clopidogrel. Propensity-score matching created 80 matched pairs. Adjusted comparisons between groups showed similar en bloc resection rates (95.1% with saline–epinephrine vs. 98.0% with hypertonic saline). There were no significant differences in adverse events (immediate EMR bleeding, post-EMR bleeding, perforation, or mortality) between groups. Multivariate analyses revealed that polyp size over 10 mm was associated with an increased risk of immediate EMR bleeding (odds ratio 12.1, 95% confidence interval 2.0–74.0; P = 0.001). Conclusions Two tested solutions in colorectal EMR were considered to be both safe and effective in patients taking antithrombotic agents.