Background. Antibiotic prophylaxis for surgical site infections (SSIs) for breast surgery is widespread, but the benefit in clean surgical cases is not well defined. Methods. A retrospective analysis of 855 patients undergoing elective, nonreconstructive breast operations was performed, with 401 patients receiving no antibiotics and 454 patients receiving a single dose of preoperative antibiotic. Results. Administration of a preoperative antibiotic did not decrease the SSI rate. In this community-based study, antibiotic use practices varied considerably by surgeon. In univariate analyses, SSI rates appeared to increase with prophylactic antibiotic use (12% SSI with antibiotics versus 4% without, p < 0.0001), likely because the use of underdosed antibiotics was associated with higher rates of SSI (13.2% SSI with cefazolin 1 gram, p < 0.0001, and 15.4% SSI with clindamycin 300 mg or less, p = 0.0269). Methicillin-resistant Staphylococcus aureus was the most common isolate from SSI cultures, 31.8% (7 of 22). In multivariable analyses, increased risk of SSI was associated with BMI > 25 kg/m2 (OR: 1.08, 95% CI: 1.04–1.11, p < 0.0001). Conclusion. The administration of a single dose of preoperative antibiotic did not decrease the rate of SSI in this large series of patients undergoing clean breast operations. BMI >25 kg/m2 and the use of an inadequate dose of antibiotics for prophylaxis may increase risk of SSI.

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