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Objective: Perioperative antibiotic prophylaxis in patients undergoing surgery for maxillofacial fractures is standard practice. However, the use of postoperative antibiotic prophylaxis remains controversial. This systematic review and meta-analysis sought to evaluate the effect of postoperative antibiotic therapy on the incidence of surgical site infection (SSI) in patients with maxillofacial fractures., Methods: MEDLINE, Embase, and the Cochrane Library were searched from inception through October 2017. Randomized controlled trials (RCTs) and cohort studies evaluating the efficacy of pre-, peri-, and postoperative antibiotic prophylaxis in preventing SSI in maxillofacial fractures were included. Data were extracted from studies using a standardized data collection form, with two reviewers independently performing extraction and quality assessment for each study. Risk ratios (RRs) for SSI were pooled using a random-effects model., Results: Among 2,150 potentially eligible citations, 13 studies met inclusion criteria and provided data to be included in a meta-analysis. The addition of postoperative antibiotic prophylaxis to a standard preoperative and/or perioperative antibiotic regimen showed no significant difference in the risk of SSI (RR = 1.11 [95% CI: 0.86-1.44], P > .1). There were also no differences in the risk of SSI when restricting the analysis to mandibular fractures (eight studies, RR = 1.22 [95% CI: 0.92-1.62]) or open surgical techniques (eight studies, RR = 1.02 [95% CI: 0.62-1.67]). A sensitivity analysis did not find any significant differences in risk when restricting to RCTs (seven trials, RR = 1.00 [95% CI: 0.61-1.67]) or cohort studies (six studies, RR = 1.21 [95% CI: 0.89-1.63])., Conclusions: Our findings, along with the available evidence, does not support the routine use of postoperative antibiotic prophylaxis in patients with maxillofacial fractures. Avoiding the unnecessary use of antibiotic therapy in the postoperative period could have important implications for healthcare costs and patient outcomes. Laryngoscope, 129:82-95, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)