BACKGROUND:: The risk of post-operative Clostridium difficile infection in patients receiving preoperative oral antibiotics remains controversial and a potential barrier for implementation. OBJECTIVES:: To determine the association between preoperative oral antibiotics and the incidence of post-operative Clostridium difficile infection in patients undergoing colorectal surgery. DATA SOURCES:: Medline, PubMed (not Medline), Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science were searched for articles published up to September 2018. STUDY SELECTION:: Randomized controlled trials (RCT) and observational studies that compared bowel preparation regimens in adult patients who underwent colorectal surgery were selected. MAIN OUTCOME MEASURE:: The incidence of post-operative Clostridium difficile infection in adults receiving oral antibiotics vs no oral antibiotics was used as primary outcome. Odds ratios were pooled using generalized linear/mixed effects models. RESULTS:: Fourteen RCTs and 13 cohort studies comparing bowel preparation with oral antibiotics to those without oral antibiotics were identified. The pooled odds ratio from 4 eligible RCTs was suggestive of a greater odds of Clostridium difficile infection in the oral antibiotic group (OR 4.46; 95%CI: 0.96-20.66); however, the absolute incidence of Clostridium difficile infection was extremely low (total 11 events among 2,753 patients). The pooled odds ratio from 6 eligible cohort studies did not demonstrate a significant difference in the odds of Clostridium difficile infection (OR 0.88; 95%CI: 0.51-1.52); again, a very low absolute incidence of Clostridium difficile infection was identified (total 830 events among 59,960 patients). LIMITATIONS:: This meta-analysis was limited by the low incidence of Clostridium Difficile infection reported in the studies and the low number of RCTs included. CONCLUSIONS:: The incidence of Clostridium difficile infection in patients who undergo colorectal surgery is very low, regardless of bowel preparation regimen used. Considering the beneficial role of oral antibiotics in reducing surgical site infection, the fear for Clostridium difficile infection is not sufficient to omit OA in this setting.