This chapter is devoted to antithrombotic therapy for peripheral artery occlusive disease as part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading see the “Grades of Recommendation” chapter by Guyatt et al, CHEST 2008; 133:123S–131S). Among the key recommendations in this chapter are the following: We recommend lifelong antiplatelet therapy in comparison to no antiplatelet therapy in pulmonary artery disease (PAD) patients with clinically manifest coronary or cerebrovascular disease (Grade 1A), and also in those without clinically manifest coronary or cerebrovascular disease (Grade 1B). In patients with PAD and intermittent claudication, we recommend against the use of anticoagulants (Grade 1A). For patients with moderate to severe disabling intermittent claudication who do not respond to exercise therapy, and who are not candidates for surgical or catheter-based intervention, we recommend cilostazol (Grade 1A). We suggest that clinicians not use cilostazol in those with less-disabling claudication (Grade 2A). In patients with short-term (< 14 days) arterial thrombosis or embolism, we suggest intraarterial thrombolytic therapy (Grade 2B), provided they are at low risk of myonecrosis and ischemic nerve damage developing during the time to achieve revascularization. For patients undergoing major vascular reconstructive procedures, we recommend IV unfractionated heparin (UFH) prior to the application of vascular cross clamps (Grade 1A). For all patients undergoing infrainguinal arterial reconstruction, we recommend aspirin (75–100 mg, begun preoperatively) [Grade 1A]. For routine autogenous vein infrainguinal bypass, we recommend aspirin (75–100 mg, begun preoperatively) [Grade 1A]. For routine prosthetic infrainguinal bypass, we recommend aspirin (75–100 mg, begun preoperatively) [Grade 1A]. In patients undergoing carotid endarterectomy, we recommend that aspirin, 75–100 mg, be administered preoperatively and continued indefinitely (75–100 mg/d) [Grade 1A]. In nonoperative patients with asymptomatic carotid stenosis (primary or recurrent), we suggest that dual antiplatelet therapy with aspirin and clopidogrel be avoided (Grade 1B). For all patients undergoing lower-extremity balloon angioplasty (with or without stenting), we recommend long-term aspirin, 75–100 mg/d (Grade 1C).