BACKGROUND: Recent guidelines recommend prolonged thromboprophylaxis after esophagectomy due to cancer. However, to our knowledge, no previous studies have examined if prolonged prophylaxis is superior to standard in-hospital prophylaxis. OBJECTIVES: We aimed to perform the first clinical randomized study testing the efficacy of a prolonged 1-month thromboprophylaxis with low-molecular-weight heparin vs the standard treatment. METHODS: The study was an open-label, randomized, controlled trial including patients undergoing esophagectomy. The primary endpoint was the difference in prothrombin fragment 1 + 2 (F1 + 2) levels 1 month after surgery between the standard group and the intervention group. The secondary endpoints were the incidence of venous thromboembolic events and mortality. RESULTS: The study was terminated before reaching the expected sample size of 100 patients due to low accrual. We included 79 patients. At follow-up 1 month after surgery, F1 + 2 levels did not differ between the standard group and the intervention group (P = .41). Incidence of venous thrombosis was similar in the 2 groups, with 13% in the standard group and 15% in the intervention group. Preoperative F1 + 2 levels were significantly higher in patients who developed a venous thrombosis within 1 month after surgery than in those who did not (P = .01). The odds ratio of venous thromboembolism per 50 pmol/L increase in F1 + 2 was 1.64 (95% CI, 1.17-2.54). No patients died within 1 month after surgery. CONCLUSION: No benefit of prolonged thromboprophylaxis after esophagectomy was found. Preoperative F1 + 2 levels were found to be a predictor for the incidence of postoperative thromboembolism.