Surgical site infection is an actual problem of orthopaedic surgery. Despite considerable efforts that have been done during last several decades (e.g. improvements in surgical techniques, preoperative preparation of the surgical site, infection-control practice, use of preventive antibiotics) surgical site infection still affects about 0.5-2% of patients after closed fracture surgery or insertion of prosthetic devices. They are associated with substantial morbidity and mortality. The adherence to the principles of rationale preventive antibiotic therapy has an important role in the prevention of the surgical infection. In addition, it is well known that inappropriate use of antibiotic promote development of resistance, superinfections and increase the cost of the treatment. This paper focuses on the basic principles of rational use of antibiotics, i.e. appropriate selection of drug, dose, and duration of treatment in the prevention of surgical site infections in orthopaedic surgery.