Background: Surgical site infections after breast surgery range from 1 to 16%. Both the American Society of Breast Surgeons (ASBrS) and the American Association of Plastic Surgeons guidelines lack clarity on postoperative antibiotic prophylaxis (AP) after mastectomy. We surveyed the ASBrS membership to understand their practice patterns of AP after mastectomy and familiarity with ASBrS guidelines. Methods: A self-designed, 19-question survey was emailed to all 2934 ASBrS members. Information was obtained on the participants’ training, familiarity with ASBrS guidelines, and practices of prescribing perioperative AP after mastectomy with/without reconstruction and with indwelling drains. Results: In total, 556 (19%) responses were analyzed. Half were fellowship-trained breast surgeons/surgical oncologists (50.2%), with 55.6% having practiced for > 15 years and 66.9% in community/private practice. Only 53.6% reported familiarity with ASBrS guidelines for perioperative AP. Most (> 90%) surgeons reported “always” placing drains after mastectomy and “always” prescribing preoperative AP. Postoperatively, preference for continuing AP in cases with drains in place varied by procedure: 7.7% when no reconstruction, 29.1% when autologous-only, and 52.5% when implant reconstruction. Academic surgeons were less likely than surgeons in community/private practice to continue postoperative AP, whether for the duration of indwelling drains (5.1% versus 9.4%) or even till 7 days postoperatively (0.6% versus 3.2%) (p < 0.05). Conclusions: Surgeons uniformly adhere to ASBrS guidelines for preoperative AP. However, there is wide variation in AP postoperatively in patients with/without reconstruction and with indwelling drains. Our results highlight the need for high-quality evidence based on which guidelines must be updated, and the need to familiarize surgeons with current guidelines.