Antibiotic prophylaxis for maxillofacial surgical wounds remains common practice. Surgeons must weigh the risks (e.g., Clostridium difficile colitis) against the benefits before administering antibiotics for any reason and the relative risk and morbidity of C difficile colitis against those of a potential postoperative wound infection. In addition, the possibility of C difficile infection as a complication of perioperative antibiotic prophylaxis should be discussed with patients before surgery, especially those with concomitant baseline risk factors. This report describes the case of a young healthy patient with few risk factors for C difficile infection who received a standard perioperative course of antibiotic therapy. Subsequently, the patient developed severe fulminant C difficile infection that required a protracted hospital admission, subtotal colectomy, and ileostomy. This case underscores that antibiotic prophylaxis continues in widespread use and is not benign therapy.