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To investigate whether implementing a bundle, defined as a set of evidence-based practices performed collectively, can reduce 30-day surgical site infections.Baseline surgical site infection rates were determined retrospectively for cases of open uterine cancer, ovarian cancer without bowel resection, and ovarian cancer with bowel resection between January 1, 2010, and December 31, 2012, at an academic center. A perioperative bundle was prospectively implemented during the intervention period (August 1, 2013, to September 30, 2014). Prior established elements were: patient education, 4% chlorhexidine gluconate shower before surgery, antibiotic administration, 2% chlorhexidine gluconate and 70% isopropyl alcohol coverage of incisional area, and cefazolin redosing 3–4 hours after incision. New elements initiated were: sterile closing tray and staff glove change for fascia and skin closure, dressing removal at 24–48 hours, dismissal with 4% chlorhexidine gluconate, and follow-up nursing phone call. Surgical site infection rates were examined using control charts, compared between periods using χ2 or Fisher exact test, and validated against the American College of Surgeons National Surgical Quality Improvement Program decile ranking.The overall 30-day surgical site infection rate was 38 of 635 (6.0%) among all cases in the preintervention period, with 11 superficial (1.7%), two deep (0.3%), and 25 organ or space infections (3.9%). In the intervention period, the overall rate was 2 of 190 (1.1%), with two organ or space infections (1.1%). Overall, the relative risk reduction in surgical site infection was 82.4% (P=.01). The surgical site infection relative risk reduction was 77.6% among ovarian cancer with bowel resection, 79.3% among ovarian cancer without bowel resection, and 100% among uterine cancer. The American College of Surgeons National Surgical Quality Improvement Program decile ranking improved from the 10th decile to first decile; risk-adjusted odds ratio for surgical site infection decreased from 1.6 (95% confidence interval 1.0–2.6) to 0.6 (0.3–1.1).Implementation of an evidence-based surgical site infection reduction bundle was associated with substantial reductions in surgical site infection in high-risk cancer procedures.