Objective The surgical site infection (SSI) rate in vascular surgery after groin incision for lower extremity revascularization can lead to significant morbidity and mortality. This trial was designed to study the effect of negative pressure wound therapy (NPWT) on SSI in closed groin wounds after lower extremity revascularization in patients at high risk for SSI. Methods A single-center, randomized, controlled trial was performed at an academic tertiary medical center. Patients with previous femoral artery surgical exposure, body mass index of >30 kg/m2 or the presence of ischemic tissue loss were classified as a high-risk patient for SSI. All wounds were closed primarily and patients were randomized to either NPWT or standard dressing. The primary outcome of the trial was postoperative 30-day SSI in the groin wound. The secondary outcomes included 90-day SSI, hospital duration of stay, readmissions or reoperations for SSI, and mortality. Results A total of 102 patients were randomized between August 2014 and December 2015. Patients were classified as at high risk owing to the presence of previous femoral artery cut down (29%), body mass index of >30 kg/m2 (39%) or presence of ischemic tissue loss (32%). Revascularization procedures performed included femoral to distal artery bypass (57%), femoral endarterectomy (18%), femoral to femoral artery crossover (17%), and other procedures (8%). The primary outcome of 30-day SSI was 11% in NPWT group versus 19% in standard dressing group (P =.24). There was a statistically significant shorter mean duration of hospital stay in the NPWT group (6.4 days) compared with the standard group (8.9 days; P =.01). There was no difference in readmission or reoperation for SSI or mortality between the two groups. Conclusions This study demonstrated a nonsignificant lower rate of groin SSI in high-risk revascularization patients with NPWT compared with standard dressing. Owing to a lower than expected infection rate, the study was underpowered to detect a difference at the prespecified level. The NPWT group did show significantly shorter mean hospital duration of stay compared with the standard dressing group.