Rivaroxaban, a non-vitamin K antagonist oral anticoagulant, is superior to enoxaparin for the prevention of venous thromboembolism (VTE) during the period of immobilization after patients undergo lower-limb non-major orthopaedic surgery. In Europe, thromboprophylaxis with a low-molecular-weight heparin, such as enoxaparin, is recommended after this form of surgery in patients who are at risk of thrombosis, whereas thromboprophylaxis is not currently recommended in the USA. In the PRONOMOS trial, 3,604 patients undergoing lower-limb non-major orthopaedic surgery were randomly assigned to receive rivaroxaban therapy or enoxaparin therapy. The primary end point of major VTE occurred in 0.2% and 1.1% of patients in each group, respectively (risk ratio 0.25, 95% CI 0.09–0.75, P < 0.001 for non-inferiority, P = 0.01 for superiority). The incidence of major or non-major bleeding was not significantly different between the two groups.