Background: Colorectal surgery is associated with a high risk of surgical site infections (SSIs), with an incidence ranging from 16.9% to 20%, and SSIs are associated with significant morbidity and mortality, prolonged length of hospitalization, and increased health care costs. Staphylococcal decolonization is an attempt to alter the microbiome to prevent staphylococcal and other skin flora from accessing the surgical site, and This practice effectively reduces SSIs in orthopedic, neurologic, and cardiac surgeries. A staphylococcal decolonization protocol was enacted in colorectal surgeries at our institution beginning in October 2016. We compared patient outcomes between patients who did and did not undergo preoperative staphylococcal decolonization. Methods: All patients undergoing nonemergent NHSN-defined colorectal procedures from July 2015 until June 2019 at a tertiary-care medical center were included in this retrospective study. Staphylococcal decolonization was performed using chlorhexidine 2% body wash solution, mupirocin nasal ointment, and chlorhexidine 0.12% oral rinse all twice daily for 5 days prior to surgery. All SSIs were defined by NSHN criteria. The primary outcome was SSI, and secondary outcomes were superficial wound infection (SIP) and organ-space infection (IAB). Predictive variables included decolonization status (yes or no), age, gender, body mass index, procedure duration, American Society of Anesthesiologists (ASA) score, diabetes, smoking, and surgical oncology service. Surgical antimicrobial prophylaxis with cefazolin and metronidazole OR cefoxitin, and chlorhexidine skin preparation were standard throughout the study period. Univariate analysis was performed using a χ2 or t test. Multivariable logistic regression was performed to control for all clinically important variables above. All statistical analyses were done using SAS version 9.4 software (Cary, NC). Results: In total, 1,139 patients underwent nonemergent colorectal surgery from July 2015 to June 2019. There were 74 SSIs: 42 IABs and 32 SIPs. Decolonization was performed in 332 of 1,139 cases (29%). There was no difference in overall SSIs between those decolonized and not decolonized (P = .50). However, SIPs were reduced in the group receiving decolonization: 1.2% (4 of 332) versus 3.5% (28 of 807) (P = .04. When controlling for known SSI risk factors, those not receiving decolonization remained at increased risk of SIPs (OR, 3.79; 95% CI, 1.14–12.61; P = .03. Conclusions: Staphylococcal decolonization may prevent a subset of SSIs in patients undergoing colorectal surgery.Funding: NoneDisclosures: Michelle Doll reports a research Grant from Molnlycke Healthcare.