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Numerous techniques are used to prevent infection after immediate implant-based breast reconstruction. Postoperative antibiotic prophylaxis is commonly prescribed to decrease the risk of reconstructive failure, despite conflicting evidence regarding its effectiveness. The authors studied whether postoperative antibiotic prophylaxis decreases the risk of infection-related explantation in the setting of immediate prosthesis-based breast reconstruction.Using Truven MarketScan databases, the authors identified all patients who underwent immediate implant reconstruction between January of 2010 and June of 2014 with at least 6 months of follow-up. Postoperative antibiotic prophylaxis was defined as any oral antibiotic course to be taken postoperatively based on prescriptions filled within 14 days preoperatively through 24 hours after discharge. Reconstructive failure, defined as explantation because of infection, was the primary outcome. Secondary outcomes of interest included wound complications, infection, and readmission for infection. Multivariable regression analyses controlled for demographic variables/comorbidities.Of the 7443 patients, 6049 (81 percent) filled prescriptions for postoperative antibiotic prophylaxis. These patients were equally likely to develop a wound complication (OR, 0.93; 95 percent CI, 0.71 to 1.23) or infection (OR, 0.89; 95 percent CI, 0.70 to 1.14), undergo explantation because of infection (OR, 0.82; 95 percent CI, 0.57 to 1.18), or require readmission for infection (OR, 1.21; 95 percent CI, 0.82 to 1.78) compared with those who did not receive antibiotics. There was no significant difference in the risk of infection-related outcomes based on postoperative antibiotic prophylaxis duration.Postoperative antibiotic prophylaxis was not associated with a reduced risk of infection or explantation following prosthesis-based breast reconstruction. Given rising rates of antibiotic resistance, focusing instead on technical considerations and the management of comorbid conditions may more effectively enhance the safety of breast reconstruction.Therapeutic, III.