Objective Surgical site infection (SSI) after open lower extremity bypass (LEB) is a serious complication leading to an increased rate of graft failure, hospital readmission, and health care costs. This study sought to identify predictors of SSI after LEB for arterial occlusive disease and also potential modifiable factors to improve outcomes. Methods Data from a statewide cardiovascular consortium of 35 hospitals were used to obtain demographic, procedural, and hospital risk factors for patients undergoing elective or urgent open LEB between January 2012 and June 2015. Bivariate comparisons and targeted maximum likelihood estimation were used to identify independent risk factors of SSI. Adjusted odds ratios (ORs) were calculated for patient demographics, comorbidities, operative details, and hospital-level factors. Results Our study population included 3033 patients who underwent 703 femoral-femoral bypasses, 1431 femoral-popliteal bypasses, and 899 femoral-distal vessel bypasses. An SSI was diagnosed in 320 patients (10.6%) ≤30 days after the index operation. Adjusted patient and procedural predictors of SSI included renal failure currently requiring dialysis (OR, 4.35; 95% confidence interval [CI], 3.45-5.47; P <.001), hypertension (OR, 4.29; 95% CI, 2.74-6.72; P <.001), body mass index ≥25 kg/m2 (OR, 1.78; 95% CI, 1.23-2.57; P =.002), procedural time >240 minutes (OR, 2.95; 95% CI, 1.89-4.62; P <.001), and iodine-only skin preparation (OR, 1.73; 95% CI, 1.02-2.91; P =.04). Hospital factors associated with increased SSI included hospital size <500 beds (OR, 2.22; 95% CI, 1.09-4.55; P =.028) and major teaching hospital (OR, 1.66; 95% CI, 1.07-2.58; P =.024). SSI resulted in increased risk of major amputation and surgical reoperation (P <.01), but did not affect 30-day mortality. Conclusions SSI after LEB is associated with an increase in rate of amputation and reoperation. Several patient, operative, and hospital-related risk factors that predict postoperative SSI were identified, suggesting that targeted improvements in perioperative care may decrease complications and improve vascular patient outcomes.