PURPOSE: To investigate the necessity and usefulness of prophylactic postoperative antibiotics in patients undergoing enucleation or ocular evisceration. METHODS: A retrospective, multicenter, comparative case series was designed. After obtaining Institutional Review Board authorization, a medical records' review was conducted. Demographics, indication for surgery, surgical technique, postoperative antibiotic dosing, and postoperative course were evaluated. Records were grouped according to antibiotic protocols, and presence or absence of postoperative wound infection (orbital cellulitis) was recorded. Rates of postoperative infection were analyzed statistically. RESULTS: Between 1996 and 2011, 666 evisceration or enucleation surgeries were conducted at 4 institutions. Six hundred forty-eight records were available for analysis, of which 4 were excluded due to insufficient follow-up data. All the remaining 644 patients received a single, perioperative, intravenous dose of antibiotics. Five hundred seventy-eight patients (90%) received an orbital implant, while 66 (10%) did not. Three hundred eighty-one patients (59%) received postoperative antibiotics, and 263 patients (41%) did not. Two cases were identified with signs suggestive of infection, but no culture-positive infections were found, and no patient was admitted to the hospital for management. Of the 2 suspicious cases, 1 was found in the group that received postoperative antibiotics (group 1) and 1 in the group that did not receive postoperative antibiotics (group 2). No statistically significant difference in postoperative infection rate was noted between the 2 groups (p=0.52). While patients with infectious indications for surgery were more likely to receive postoperative antibiotics (p<0.001), there was no statistically significant difference in rates of infection among patients with infectious indications for surgery based on receiving or not receiving postoperative antibiotics (p=0.79), and no patients with infectious indications for surgery not receiving postoperative antibiotics developed a postoperative infection. CONCLUSIONS: This study demonstrates the clinical safety of withholding postoperative prophylactic antibiotics in orbital surgery even when implanting alloplastic material in a sterile field. Furthermore, Centers for Disease Control and Prevention guidelines mandate cessation of postoperative antibiotics within 24 hours of surgery. Surgeons are cautioned not to generalize these results to nonsterile surgery such as sinonasal or nasolacrimal surgery.