Purpose: The purpose of this study was to review the 91 failing polytetrafluoroethylene (PTFE) grafts that were treated at our institution over the past 12 years to better understand their cause and improve the diagnosis and treatment of these grafts. Methods: Eighty-five patients with 91 failing grafts were retrospectively reviewed. The 144 graft-threatening lesions associated with these grafts were characterized by location (inflow artery, outflow artery, anastomosis, or graft body) and treatment method used (surgery, balloon angioplasty, or thrombolysis). Results: Progression of atherosclerotic disease was the predominant cause of failing PTFE grafts with 43 inflow lesions and 83 outflow lesions, accounting for 87% of all lesions identified. Ten lesions (7%) were noted within the prosthetic grafts, whereas only eight (6%) lesions were noted at the anastomoses. Forty stenotic lesions 2 cm in length or less were treated with percutaneous transluminal balloon angioplasty, whereas 100 lesions were treated by patch angioplasty or graft extensions. The remaining four lesions, present within the prosthetic grafts, were treated with thrombolytic therapy. The 5-year cumulative patency rate for all failing PTFE grafts was 71%, whereas that of failing femoropopliteal PTFE grafts was 64%. The 5-year limb salvage rate for all failing PTFE grafts was 73%. Conclusions: The progression of inflow and outflow disease is the predominant cause of failing PTFE grafts, which suggests that this process is a more important cause of PTFE graft thrombosis than is generally recognized. Frequent PTFE graft surveillance may permit detection of some threatening lesions before graft thrombosis occurs and may help maintain and prolong graft patency. The enhanced 5-year patency and limb salvage rates for treated failing PTFE grafts compared with the known poor outcome after reinterventions for PTFE graft failure support the conclusion that surveillance of PTFE grafts is worthwhile.