Since coming into practice in 2010, direct oral anticoagulants (DOACs) have become an increasingly popular form of anticoagulation. However, it is unclear which form of polypectomy intervention or peri-procedural anticoagulation management is best for reducing post-polypectomy bleeding (PPB) risk in the setting of DOAC usage. The aim of our study was to assess the efficacy of polypectomy approaches and management of anticoagulation in minimizing PPB in patients on DOACs. A systematic review of electronic databases was performed through September 2019, including PubMed, MEDLINE, EMBASE, and Cochrane. Two authors independently screened manuscripts and extracted data using Covidence. We included prospective, retrospective, case-control, cohort, and randomized controlled trials that evaluated PPB in patients on DOACs who underwent colonoscopy with polypectomy. The primary outcome was overall PPB rate in patients undergoing snare polypectomy versus endoscopic mucosal resection. We compared approaches to anticoagulation which included heparin bridge, no heparin bridge, and continuation of DOAC. Random effect analyses and 95% confidence intervals (CI) were calculated for all outcomes. Between-study heterogeneity was quantified using the Q statistic and I2 (p<0.05 was considered significant). 973 citations were reviewed, of which 9 were included in the final analysis. The majority were retrospective cohort studies. In total, the studies comprised 2,977 patients with average age of 72.4 years and study follow-up period ranging from 2 to 6 years. Studies defined PPB as hematochezia requiring endoscopic hemostasis occurring 14 to 30 days post endoscopy. Endoscopic submucosal dissection was associated with a significantly higher rate of PPB compared to snare polypectomy. There was a tendency towards higher PPB rates in hot snare versus cold snare polypectomy cases, though this did not reach statistical significance. There were no statistically significant bleeding rates amongst various anticoagulation management strategies. However, PPB effects sizes did tend to be larger in cases where anticoagulation was continued peri-procedurally (Table 1). There was insufficient data to determine the role of prophylactic clips after polypectomy. PPB is a serious adverse effect of colonoscopy. We found that in patients on DOACs, performing endoscopic submucosal dissection is associated with higher PPB rates compared to snare polypectomy. However, for patients at high risk of thromboembolism, our results suggest that continuation of DOAC may not increase the risk of PPB as compared to heparin bridging or discontinuation of anticoagulation altogether. More high-quality studies are needed to further discern amongst various anticoagulation and PPB-prevention strategies.