Background/Aim: This study aimed to assess whether low-molecular-weight heparin (LMWH) is effective and safe in preventing postoperative venous thromboembolism (VTE) in patients undergoing esophageal cancer surgery. Patients and Methods: In this single-institution, prospective, randomized trial, 73 patients with esophageal cancer undergoing esophagectomy were randomly divided into the enoxaparin group (E group) and intermittent pneumatic compression group (I group). The primary endpoint was efficacy of enoxaparin, and secondary endpoints were evidence of bleeding and serum anti-Xa activity in the E group. Results: The E group comprised 42 patients and the I group comprised 31 patients. Deep vein thrombosis was observed in 0 (0%) patients in the E group and 7 (22.6%) patients in the I group (p=0.002). Soluble fibrin monomer complex was significantly lower in the E versus I group on day 8 (p<0.001). D-dimer was significantly lower in the E versus I group on days 2, 8, and 15 (p=0.008, p<0.001, p<0.001, respectively). Conclusion: VTE was significantly reduced by using enoxaparin. Venous thromboembolism (VTE) is the second leading cause of death in cancer patients receiving outpatient chemotherapy (1). As represented by Trousseau's syndrome, multiple pathophysiologic mechanisms contribute to the hypercoagulability associated with cancer (2). The Japan VTE Treatment Registry revealed the maximal risk factor for VTE to be cancer (3). Major surgery for cancer located in the abdomen or chest is associated with a high incidence of VTE, as the major postoperative complication, including deep venous thrombosis (DVT) and pulmonary thromboembolism (PTE) (4). According to previous reports, the incidence of symptomatic VTE after esophagectomy is reported to range from 2.9 to 3.8%, (5, 6), whereas that of asymptomatic VTE after esophagectomy ranges from 5.9 to 23.3% (7-9). Thus, the prevalence of asymptomatic VTE is not small after esophageal cancer surgery, and occasionally, unfortunate outcomes can occur; thus, prevention of VTE is very important. The use of low-molecular-weight heparin (LMWH) was recommended to prevent VTE after cancer surgery (10). Lee et al. reported that in patients with cancer and acute VTE, LMWH was more effective than an oral anticoagulant in reducing the risk of recurrent VTE, without increasing the risk of bleeding (11). However, an optimal strategy of thromboprophylaxis for esophagectomy has not been formulated, and to the best of our knowledge, there are no reports comparing the effects of LMWH through randomized controlled trials (RCTs). Enoxaparin is a LMWH that functions as an anticoagulant agent by forming a complex with antithrombin 3 (AT-III) and promoting AT-III activity. The evidence for enoxaparin in orthopedic, gynecologic malignancy and abdominal or pelvic malignancy has already been established (12-14). In 2615 This article is freely accessible online.