INTRODUCTION: D-dimer is widely used in clinical pretests for venous thromboembolism exclusion, and its elevation suggests the presence of thrombus. The extent of hypercoagulability after colorectal surgery has not been systematically compared between patients who have undergone laparoscopic surgery and open surgery. The present study measured D-dimer levels sequentially in patients undergoing colorectal surgery and compared the extent of hypercoagulability between laparoscopic surgery and open surgery. METHODS: A prospective cohort study involving 169 patients who underwent resection of colorectal cancer at Saitama Medical Center, Dokkyo Medical University, was conducted between January 2013 and September 2014. To measure D-dimer level, peripheral blood was obtained on postoperative day (POD) 1, POD4, and POD7. Enoxaparin sodium was administered twice daily as the routine prophylactic anticoagulant therapy on POD2 to 7. RESULTS: D-dimer levels on POD1, POD4, and POD7 were significantly higher after open surgery than after laparoscopic surgery. Older age, pathologically advanced stage cancer, greater intraoperative blood loss and higher preoperative D-dimer levels were significantly associated with higher D-dimer levels on POD1, POD4, and POD7. Patients who completed the course of postoperative enoxaparin injections had significantly lower D-dimer levels on POD7 than those who did not receive postoperative enoxaparin injections. Multiple regression analyses of postoperative D-dimer level showed that laparoscopic surgery was a significant and independent factor affecting D-dimer level on POD4 and POD7. CONCLUSION: This study showed that postoperative D-dimer levels were lower after laparoscopic surgery than after open surgery. The limited invasiveness of laparoscopic surgery may be beneficial to reduce the risk of postoperative deep vein thrombosis.