Our objective was to evaluate the efficacy and safety of natural hirudin and low molecular weight heparin (LMWH) in the prevention of perioperative deep venous thrombosis (DVT) in elderly patients with intertrochanteric fracture. From June 2014 to June 2017, 96 patients with intertrochanteric fractures were treated with proximal femoral nail antirotation (PFNA) were randomly divided into two groups. For DVT prevention, 45 patients were treated with oral natural hirudin and subcutaneous LMWH-calcium (test group) and 51 patients were treated with subcutaneous LMWH-calcium (control group). The mean intraoperative bleeding, wound drainage and incisional hematoma were higher in the test group, with no significant differences between the groups. There were significant differences in distal intramuscular venous thrombosis (P = 0.043). Both activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT) lengthened in both groups postoperatively, and there was a significant difference between the two groups two weeks postoperatively. D-dimer were significantly different and platelet count (PLT) did not differ between groups two weeks postoperatively. In elderly patients with unilateral intertrochanteric fracture after PFNA on anticoagulant therapy, the combination of natural hirudin and LMWH was more effective than that of LMWH-calcium alone, with no significant difference with regard to safety.