Fondaparinux and enoxaparin are useful for preventing venous thromboembolism after total knee arthroplasty (TKA), but both drugs have associated complications. The purpose of this study was to clarify the risks associated with use of these drugs in Japanese patients who underwent TKA.A total of 575 patients (935 knees) underwent TKA and were retrospectively reviewed; 277 patients (454 knees) were treated with fondaparinux and 298 patients (481 knees) were treated with enoxaparin. The authors investigated the incidences of deep venous thrombosis of the lower limbs and pulmonary embolism to evaluate venous thromboembolism, knee enlargement compared with the preoperative size, incidence of subcutaneous knee hematoma, and other complications. No significant differences were observed between the 2 drugs regarding the incidences of deep venous thrombosis and pulmonary embolism. However, fondaparinux use resulted in knee enlargement (P<.0005) and subcutaneous hematoma of the knee (P=.035) significantly more often than enoxaparin use. Conversely, enoxaparin use significantly caused the elevation of alanine aminotransferase (one of the liver enzymes) at a higher rate than fondaparinux (30.1% vs 8.3%, respectively; P<.0001). However, the increased alanine aminotransferase levels were transient, and no patient exhibited symptoms of abnormal liver function, such as jaundice or cutaneous pruritus.Fondaparinux and enoxaparin were both effective in preventing venous thromboembolism in Japanese patients undergoing elective TKA. However, both drugs had some adverse effects. It is important to be aware of these potential risks when prescribing these drugs.