Background/Aims: The safety of gastric endoscopic submucosal dissection (ESD) in users of a P2Y12 receptor antagonist (P2Y12RA) under current guidelines has not been verified. Methods: Patients treated by gastric ESD at Okayama University Hospital between January 2013 and December 2020 were registered. The postoperative bleeding rates of patients (group A) who did not receive any antithrombotic drugs; patients (group B) receiving aspirin or cilostazol monotherapy; and P2Y12RA users (group C) those on including monotherapy or dual antiplatelet therapy were compared. The risk factors for post-ESD bleeding were examined in a multivariate analysis of patient background, tumor factors, and antithrombotic drug management. Results: Ultimately, 1,036 lesions (847 patients) were enrolled. The bleeding rates of group B and C were significantly higher than that of group A (p=0.012 and p<0.001, respectively), but there was no significant difference between group B and C (p=0.11). The postoperative bleeding rate was significantly higher in dual antiplatelet therapy than in P2Y12RA monotherapy (p=0.014). In multivariate analysis, tumor diameter ≥12 mm (odds ratio [OR], 4.30; 95% confidence interval [CI], 1.99 to 9.31), anticoagulant use (OR, 4.03; 95% CI, 1.64 to 9.86), and P2Y12RA use (OR, 3.40; 95% CI, 1.07 to 10.70) were significant risk factors for postoperative bleeding. Conclusions P2Y12RA use is a risk factor for postoperative bleeding in patients who undergo ESD even if receiving drug management according to guidelines. Dual antiplatelet therapy carries a higher risk of bleeding than monotherapy.