Background: Pre-operative oral antibiotics administered the day prior to elective colectomy have been shown to decrease the incidence of surgical site infections (SSI) if a mechanical bowel prep (MBP) is used. Recently, the role for mechanical bowel prep has been challenged as being unnecessary and potentially harmful. We hypothesize that if MBP is omitted, oral antibiotics do not alter the incidence of SSI following colectomy. Methods: We selected patients who underwent an elective segmental colectomy from the 2012 and 2013 National Surgical Quality Improvement Program colectomy procedure targeted database. Indications for surgery included colon cancer, diverticulitis, inflammatory bowel disease, or benign polyp. Patients who received mechanical bowel prep were excluded. The primary outcome measured was surgical site infection, defined as the presence of superficial, deep or, organ space infection within 30 d from surgery. Results: A total of 6,399 patients underwent elective segmental colectomy without MBP. The incidence of SSI differed substantially between patients who received oral antibiotics, versus those who did not (9.7% vs. 13.7%, p=0.01). Multivariate analysis indicated that age, smoking status, operative time, perioperative transfusions, oral antibiotics, and surgical approach were associated with post-operative SSI. When controlling for confounding factors, the use of pre-operative oral antibiotics decreased the incidence of surgical site infection (odds ratio=0.66, 95% confidence interval=0.48-0.90, p=0.01). Conclusion: Even in the absence of mechanical bowel prep, pre-operative oral antibiotics appear to reduce the incidence of surgical site infection following elective colectomy.