Low-molecular-weight heparin has been studied extensively in total knee arthroplasty (TKA) and provides highly effective and safe prophylaxis against deep venous thrombosis (DVT). Low-molecular-weight heparin received the highest rating (A1) in the American College of Chest Physicians recommendations for DVT prophylaxis after elective TKA. Prevalence of DVT with low-molecular-weight heparin prophylaxis was 33% in TKA data pooled from six randomized studies, with a proximal DVT rate of 7.1%. A metaanalysis reported a 2.4% rate of major bleeding with low-molecular-weight heparin. Low-molecular-weight heparin, given by subcutaneous injection, can be started before surgery or after surgery. A synthetic pentasaccharide (fondaparinux), which received an A1 rating in the American College of Chest Physicians recommendations, also is available. As with all treatments, the benefit must be considered against the risk when using these anticoagulants.