Hospitalization and surgery are associated with an increased risk of deep vein thrombosis and pulmonary embolism. Low molecular weight heparins (LMWH) are effective in venous thromboembolism (VTE) prevention and have been the treatment of choice during many years. In recent years direct oral anticoagulants (DOAC's) have also been approved for VTE prevention in patients undergoing elective orthopedic surgery. Randomized controlled clinical trials (RCT's) on the use of DOAC's for VTE prevention in non-orthopedic surgery are scarce, whereas RCT's on DOACs in acute ill medical patients do not favor its use. Although DOAC's have a similar efficacy compared with LMWH, their use is associated with an increased risk of major bleeding. As a result, in primary VTE prevention the role of DOAC's will probably remain limited to patients with a very low bleeding risk and a high thrombotic risk in whom an oral drug is preferred.