Background <p>Surgical site infections (SSIs) are a common complication after bimaxillary orthognathic surgery. While sulbactam/ampicillin and cefmetazole are recommended in Japan, alternatives such as ampicillin and clindamycin are also used, with limited comparative evidence. This study assessed the impact of these antibiotics on SSI incidence and related risk factors.</p> Methods <p>We retrospectively analyzed 115 patients who underwent Le Fort I and bilateral sagittal split osteotomy at the University of Osaka Dental Hospital between January 1 and December 31 in 2023. Patients were categorized into four groups based on the prophylactic antibiotic administered: sulbactam/ampicillin (<i>n</i> = 70), ampicillin (<i>n</i> = 8), cefmetazole (<i>n</i> = 25), and clindamycin (<i>n</i> = 12). The duration of antibiotic administration was standardized within each group. Clinical variables such as age, sex, body mass index, third molar extraction, temporary anchorage devices insertion, operative time, and estimated blood loss were collected and compared between groups. SSI was defined as a postoperative infection requiring antibiotic treatment occurring within 30 days (or within 1 year if implants were used).</p> Results <p>There were no significant differences in patient characteristics among the four antibiotic groups. SSI incidence was significantly higher in the ampicillin group compared to the sulbactam/ampicillin group (<i>p</i> = 0.046), while no other pairwise comparisons among the groups revealed statistically significant differences. Other clinical variables were not significantly associated with SSI occurrence.</p> Conclusion <p>Ampicillin monotherapy may be insufficient for preventing SSIs in bimaxillary orthognathic surgery. Sulbactam/ampicillin demonstrated superior efficacy, whereas cefmetazole and clindamycin showed comparable effectiveness as alternative prophylactic agents. These findings underscore the importance of selecting appropriate antibiotics to minimize postoperative infection risk.</p>