The effectiveness of defibrotide was compared with that of calcium heparin and acetylsalicylic acid (ASA) in the prevention of deep venous thrombosis (DVT) resulting from orthopedic surgery. Sixty-three patients scheduled for elective or traumatological surgery, for the most part involving the hip joint, were recruited. The patients were randomly assigned to one of the following treatment groups: defibrotide (400 mg twice daily), administered intramuscularly (n = 19); calcium heparin (5,000 IU thrice daily), administered subcutaneously (n = 25); and ASA (100 mg on alternate days), administered orally (n = 19). Administration of the drug was started one day before surgery and continued until the seventh day after surgery. Each patient was monitored daily by means of the fibrinogen uptake test. The incidence of increased uptake did not differ significantly in the three groups (defibrotide, ten out of 19; calcium heparin, ten out of 25; ASA, seven out of 19). Conversely, a trend in favor of defibrotide was noted in cases of symptomatic DVT (defibrotide, one out of 19; calcium heparin, two out of 25; ASA, four out of 19) and pulmonary embolism (defibrotide, no cases; calcium heparin, one case; ASA two cases). On the strength of these findings, defibrotide therapy qualifies as a valid alternative to conventional DVT prophylaxis in orthopedic surgery.