Surgical site infections (SSIs) are a notable cause of hospital morbidity and mortality. Antibiotic prophylaxis has demonstrated a significant reduction in infection rate in clean-contaminated surgery and in clean surgery to a limited extent. To make antibiotic prophylaxis effective it is necessary to choose the right antibiotic, to administer it preoperatively and maintain sufficient serum and tissue levels through the operation. Open issues remain: antibiotic prophylaxis duration in prosthetic surgery, its use in hernia repair, breast surgery and mini-invasive surgery.