To compare the safety and efficacy of Angio-Seal to manual compression in achieving hemostasis following direct percutaneous access of polyethylene terephthalate (PTFE) vascular bypass grafts This was an IRB-approved single institution, retrospective review of all patients undergoing endovascular evaluation and/or intervention performed on a peripheral bypass graft from June 2013 to July 2020. Cases in which the percutaneous access was not gained directly into the bypass graft, the bypass graft was not composed of PTFE, or in which closure was not obtained with either Angio-Seal or manual compression (e.g., planned primary surgical closure in collaborative hybrid cases) were excluded. Demographic data including patient age, sex, and co-morbidities, as well as procedural data including the type of procedure, type of graft accessed (femoral-femoral, axillary-femoral, femoral-popliteal or femoral-distal), method of access closure, peri-procedural anticoagulation and antibiotic use, and data regarding 30-day post-procedural complications were collected. For the purposes of this study, an ‘angiogram with intervention’ broadly includes all variety of angioplasty and stenting. A total of 373 cases involving lower extremity bypass interventions were reviewed. Of these, 119 unique cases resulted in 154 direct punctures of a PTFE bypass which met criteria for analysis. This included diagnostic angiograms (n = 18 (12%)), angiography with intervention (n = 66 (43%)) and utilization of catheter-directed thrombolysis (n = 70 (45%)). 116 accesses were closed with Angio-Seal and hemostasis was achieved with manual compression in the remaining 38. Overall, the access complication rate of direct PTFE puncture was 5.2%, with a major complication rate of 2.6%. A total of 4 (3.4%) complications were reported in PTFE accesses closed with Angio-Seal. Of these, 2 (1.7%) were considered major complications, including an abscess requiring surgical drainage and post-deployment stenosis requiring repair. A total of 4 (10.5%) complications were reported following manual compression, of which 2 (5.3%) developed pseudoaneurysms necessitating repair, which were considered major complications. Of the 8 total reported complications, 6 (75%) arose after catheter-directed thrombolysis, and the remaining 2 following an intervention. No complications were reported following diagnostic angiography alone. Angio-Seal is safe and effective in achieving hemostasis following PTFE puncture and has a lower rate of overall and major complications.