Background and study aims: Postpolypectomy bleeding is a rare but serious adverse event. The aim of this study was to identify factors associated with the risk of severe delayed postpolypectomy bleeding. Patients and methods: This was a case-control study, comparing cases who developed hematochezia and required medical evaluation 6 hours to 14 days after colonoscopic polypectomy, and control patients who underwent polypectomy without delayed bleeding, and who were selected in approximately a 3:1 ratio. The following risk factors were specified a priori: resuming anticoagulation (within 1 week following polypectomy), aspirin use, hypertension, and polyp diameter. Results: Of the 4592 patients who underwent colonoscopy with polypectomy, 41 patients (0.9%) developed delayed postpolypectomy bleeding (cases), and 132 patients were selected as controls. The mean age was 64.3 years for cases and 65.4 years for controls. Cases presented on average 6 days after polypectomy (range 1-14 days), and 48% required blood transfusion (average 4.2 units, range 0-17). Two patients required surgery. Anticoagulation was resumed following polypectomy in 34% of cases compared with 9% of controls (OR 5.2; 95 % Cl 2.2-12.5; P < 0.001). For every 1 mm increase in polyp diameter, the risk of hemorrhage increased by 9% (OR 1.09; 95 % Cl 1.0-1.2; P = 0.008). Hypertension (OR 1.1) and aspirin use (OR 1.1) did not increase the risk of postpolypectomy bleeding. In exploratory analysis, diabetes (OR 2.5) and coronary artery disease (OR 3.0) were associated with postpolypectomy hemorrhage, but the association was no longer statistically significant once adjusted for the use of anticoagulation. Conclusions: Resuming anticoagulation following polypectomy and polyp diameter were strongly associated with increased risk of severe delayed postpolypectomy bleeding.