Purpose The purpose of this study is to determine the effect of a 3- vs. 1-day antibiotic regimen on the rate of surgical site infection (SSI) in patients undergoing orthognathic surgery at the Department of Oral and Maxillofacial Surgery in Halifax, Nova Scotia, Canada. Patients and Methods A prospective, randomized controlled trial (RCT) was conducted. All patients received 1 day of intravenous (IV) antibiotics following surgery. The patients were then randomly distributed into groups that received 2 days of additional antibiotics (Group A) or placebo (Group B). The primary outcome measured was the presence of SSI. The operating surgeon; concomitant extraction of teeth; surgical procedures performed; duration of intermaxillary fixation (IMF) and length of hospital stay were analyzed for an effect on SSI. Patients were followed for 1 year following surgery to identify SSIs that may have been diagnosed outside of our hospital. Results The trial started with 288 patients, and 117 patients were lost to follow-up. Statistical analyses were ultimately performed on those 171 patients who were adherent to the study medication regimen. Group A (n=86) and B (n=85) SSI rates were 7.0 and 17.6% (p=0.04; NNT=10), respectively. The mandible/bilateral sagittal split osteotomy (BSSO) was involved in 71% of SSIs. Intra- and post-operative surgical variables did not have a significant effect on the SSI rate. Patients were followed for 1 year following surgery, where Group A (n=46) and Group B (n=44) had an SSI rate of 4 and 25% (p<0.05), respectively. Conclusions Three days of post-operative cefazolin/cephalexin significantly reduces SSI rates compared with 1 day. However, the NNT of 10 suggests that the benefits of the extended regimen may not outweigh the risks. The high prevalence of SSIs at the mandibular/BSSO incisions may be caused by contamination with more saliva and reception of a lower blood supply than maxillary/Le Fort I incisions. Mandibular osteotomies may benefit from an extended antibiotic regimen to minimize SSI and associated complications. Other surgical variables may not require special consideration for antibiotic therapy.