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INTRODUCTION In this multi-institutional series, we aimed to determine the incidence, risk factors, and long-term outcomes of graft infection in patients post-femoropopliteal bypass. METHODS A multi-institutional database was retrospectively queried for all femoropopliteal bypass procedures from 1995-2020. Cumulative incidence function estimated the long-term rate of bypass graft infection (BGI) and Fine-Gray model was used to determine independent risk factors for BGI to account for death as a competing risk. RESULTS Over the 25-year period, 1315 femoral popliteal bypasses were identified with a median follow-up of 2.89 years (IQR 0.75-6.55). BGI was diagnosed in 34 (2.6%) patients. BGI occurred between 9 days and 11.2 years postoperatively, with a median 109 days. Estimated 1- and 5-year incidence of BGI was 2.1% (95% CI, 1.4-3.1%) and 2.8% (95% CI, 1.9-3.9%) respectively. Medical comorbidities, indications for bypass, and popliteal bypass targets (above- vs below-knee) were similar between BGI patients and all patients (p=NS each). Patients with BGI were more frequently complicated by postoperative hematoma (14.7% vs 3.7%), superficial wound infection (38.2% vs 19.2%), lymphocele/lymphorrhea (8.8% vs 2.1%), and 30-day readmission rates (47.1% vs 21.3%) (p<0.05 each). Most commonly isolated pathogens were Staphylococcus aureus (n=19, 55.9%) and polymicrobial cultures (n=5, 14.7%). Reoperation for BGI involved incision and drainage (n=7, 20.6%), graft excision without reconstruction (n=12, 35.3%), graft excision with in-line reconstruction (n=11, 32.4%), and graft excision with extra-anatomic reconstruction (n=2, 5.9%). Nine BGI patients (26.5%) ultimately required major amputation. Prosthetic bypass (subdistribution hazard ratio [SHR] 3.73 [1.64-8.51], p=0.002), postoperative hematoma (SHR 3.44 [1.23-9.61], p=0.018), and 30-day readmission (SHR 2.75 [1.27-5.44], p=0.010) were independently associated with BGI. One-year amputation-free survival was 50% (95% CI, 31.9-65.7%) after BGI. CONCLUSIONS BGI is a rare complication of femoral-popliteal bypass with significant morbidity. Graft infection is associated with the use of prosthetic grafts, postoperative hematoma, and unplanned hospital readmission. Mitigation of these risk factors may decrease the risk of this dreaded complication.