The use of systemic prophylactic antibiotics to reduce surgical-site infection in esthetic breast surgery remains controversial, although the majority of surgeons prefer to utilize antibiotics to prevent infection. Nonetheless, postoperative acute and subclinical infection and capsular fibrosis are among the most common complications following implant-based breast reconstruction. After esthetic breast augmentation, up to 2.9% of women develop infection, with an incidence rate of 1.7% for acute infections and 0.8% for late infections. After postmastectomy reconstruction (secondary reconstruction), the rates are even higher. The microorganisms seen in acute infections are Gram-positive, whereas subclinical late infections involving microorganisms are typically Gram-negative and from normal skin flora with low virulence. In primary implantation, a weight-based dosing of cefazolin is adequate, an extra duration of antibiotic cover does not provide further reduction in superficial or periprosthetic infections. Clindamycin and vancomycin are recommended alternative for patients with β-lactam allergies. The spectrum of microorganism found in late infections varies (Gram-positive and Gram-negative), and the antibiotic prophylaxis (fluoroquinolones) should be extended by vancomycin and according to the antibiogram when replacing implants and in secondary breast reconstruction, to target microorganisms associated with capsular contracture. All preoperative antibiotics should be administered <60 minutes before incision to guarantee high serum levels during surgical procedure.