Objective: A recent retrospective study showed that the ischemic consequences of femoropopliteal bypass graft occlusion were more severe with polytetrafluoroethylene (PTFE) than with vein. This study examines this conclusion and whether oral anticoagulation therapy reduces the degree of ischemia after occlusion of PTFE and vein femoropopliteal bypass grafts. Methods: Four hundred two patients who underwent femoropopliteal bypass grafting (233 PTFE and 169 vein) were randomized to a postoperative regimen of either warfarin (international normalized ratio, 1.4 to 2.8) and aspirin (WASA; 325 mg daily) therapy or aspirin alone (ASA) therapy. The grade of acute ischemia at the time of graft occlusion was assessed with the Society of Vascular Surgery recommended reporting standards (I, viable; II, threatened). Early graft occlusions (<30 days) were excluded. Results: There were 100 graft occlusions (67 PTFE and 33 vein) during a mean follow-up period of 36 months (PTFE) and 39 months (vein). Forty-eight patients were randomized to WASA therapy, and 52 were randomized to ASA therapy. The patients were well matched for age, atherosclerotic risk factors, operative indication, and preoperative ankle-brachial index. Overall, a greater percentage of the PTFE occlusions caused grade II ischemia than did the vein graft occlusions (48% versus 18%; P = .005). The ankle-brachial index at the time of graft occlusion was significantly lower in the PTFE grafts than in the vein grafts (0.28 versus 0.45; P = .001). The patients with PTFE who were undergoing WASA therapy at the time of graft occlusion had less grade II ischemia than did those patients who were undergoing ASA therapy (28% versus 55%; P = .057). However, the incidence rate of severe ischemia after graft occlusion remained greater with PTFE grafts and WASA therapy as compared with all the vein grafts (28% versus 18%). The vein graft occlusions had the same incidence rate of grade II ischemia with WASA therapy as with ASA therapy (20% versus 17%; P = 1.0). Conclusion: The ischemic consequences of femoropopliteal bypass graft occlusion are worse with PTFE than with vein. Treatment with WASA therapy lessens the severity of acute ischemia after the occlusion of PTFE graft as compared with ASA therapy but not to the degree seen with vein graft occlusion. Occlusion of femoropopliteal vein grafts is seldom accompanied by severe ischemia and is not unproved with WASA therapy.