Objective To investigate whether prophylactic anticoagulation therapy can reduce the risk of postoperative complications in patients with primary liver cancer (PLC) after hepatectomy, and to explore the influencing factors of postoperative complications. Methods The clinical data of 495 patients undergoing hepatectomy for PLC in The Third Affiliated Hospital of Naval Medical University (Second Military Medical University) from Feb. 2019 to May 2021 were collected. The patients were divided into anticoagulation group (n＝287, receiving prophylactic low-molecular-weight heparin after surgery) and conventional treatment group (n＝208). The postoperative complications were compared between the 2 groups, and the influencing factors were analyzed using logistic regression model. Results The postoperative overall complication incidence of the 495 patients after hepatectomy was 30.7% (152/495), ranking as infection (9.1%, 45/495), acute respiratory distress syndrome (ARDS; 6.5%, 32/495), bleeding (6.3%, 31/495), post-hepatectomy liver failure (PHLF; 6.1%, 30/495), and venous thromboembolism (VTE; 2.8%, 14/495). The incidence rates of postoperative VTE, ARDS, and PHLF were significantly lower in the anticoagulation group than those in the conventional treatment group (1.4% ［4/287］ vs 4.8% ［10/208］, 3.8% ［11/287］ vs 10.1% ［21/208］, and 3.8% ［11/287］ vs 9.1% ［19/208］; all P＜0.05), but there was no significant difference in the incidence of postoperative bleeding between the 2 groups (P＞0.05). Multivariate logistic regression analysis showed that age, portal hypertension, and tumor number were independent risk factors for postoperative VTE; portal hypertension, intraoperative blood loss, intraoperative blood transfusion, and preoperative procalcitonin (PCT) were independent risk factors for PHLF; ascites and preoperative bilirubin were independent risk factors for ARDS; and postoperative prophylactic anticoagulation was an independent protective factor for VTE and ARDS (all P＜0.05). Conclusion Prophylactic anticoagulation can reduce the risks of VTE, PHLF, and ARDS in PLC patients after hepatectomy, without increasing the risk of postoperative bleeding. Age, portal hypertension, number of tumors, intraoperative blood loss, intraoperative blood transfusion, ascites, preoperative PCT, and preoperative bilirubin are risk factors for postoperative complications of PLC patients after hepatectomy.