Venous thromboembolism, including pulmonary embolism and deep vein thrombosis, is a significant factor in morbidity and mortality of patients. New oral anticoagulants, such as apixaban, dabigatran, and rivaroxaban, have recently demonstrated their safety and efficacy in patients undergoing major orthopaedic surgery. Selection of the appropriate drug should be adjusted according to patient needs. Major bleeding is rare with new oral anticoagulants and is comparable with the bleeding rate associated with low-molecular-weight heparins. Clinical data indicate that therapy with apixaban and rivaroxaban was more effective compared to enoxaparin, while dabigatran has a similar efficacy to enoxaparin. Cost-effectiveness studies of new oral anticoagulants showed that these medicines offer higher efficacy with acceptable costs for the healthcare system, even saving costs in certain cases. Clinical practice in Serbia reflects considerably more frequent use of traditional anticoagulant medication therapy compared to new oral anticoagulants.