BACKGROUND Prosthetic graft infection is a major complication of peripheral vascular surgery. We investigated the experience of a single institution over 10 years with bypass grafts involving the femoral artery to determine the incidence and risk factors for prosthetic graft infection. METHODS A retrospective cohort single-institution review of prosthetic bypass grafts involving the femoral artery from 2001 to 2010 evaluated patient demographics, body mass index, comorbidities, indications, location of bypass, type of prosthetic material, case urgency, and previous ipsilateral bypass or percutaneous interventions and evaluated the incidence of graft infections, amputations, and mortality. RESULTS There were 496 prosthetic grafts identified with a graft infection rate of 3.8% (n = 19) at a mean follow-up of 27 months. Multivariable analysis showed that redo bypass (hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.2-15.0), active infection at the time of bypass (HR, 5.2; 95% CI, 1.9-14.2), female gender (HR, 4.5; 95% CI, 1.6-12.7), and diabetes mellitus (HR, 4.6; 95% CI, 1.5-14.3) were significant predictors of graft infection. Graft infection was predictive of major lower extremity amputation (HR, 9.8; 95% CI, 3.5-27.1), as was preoperative tissue loss (HR, 4.7; 95% CI, 1.8-11.9). Graft infection did not predict long-term mortality; however, chronic renal insufficiency (HR, 2.3; 95% CI, 1.6-3.4), tissue loss (HR, 1.4; 95% CI, 1.0-1.9), and active infection (HR, 2.3; 95% CI, 1.6-3.4) did. Infected grafts were removed 79% of the time. Staphylococcus epidermidis (37%) and methicillin-sensitive Staphylococcus aureus (26%) were the most common pathogens isolated. CONCLUSIONS Redo bypass, female gender, diabetes, and active infection at the time of bypass are associated with a higher risk for prosthetic graft infection and major extremity amputation but do not confer an increased risk of mortality. Autologous vein for lower extremity bypass and endovascular interventions should be considered when feasible in high-risk patients.