Objective: To investigate the relationship between D-dimer in different periods and postoperative deep venous thrombosis (DVT) in patients with early gastric cancer and premalignant lesions underwent endoscopic submucosal dissection (ESD). Methods: A retrospective cohort study was carried out, 176 patients with early gastric cancer were collected, including 117 men with an average age of (62.9±9.7) years. According to the results of vascular ultrasound examination of the lower extremities at 3 days after surgery, the patients were divided into two groups: venous thrombosis group (12 people) and non-venous thrombosis group (164 people). Collect general clinical data of patients: (1) Padua scale to calculate postoperative DVT Risk score. (2) Measure the blood D-dimer level of all patients 1 day before operation, immediately after operation and 1 day after operation. (3) Analyze the ROC curve and area under curve (AUC) of multiple variables to predict DVT after ESD. (4) Multiple regression model to analyze the relationship between D-dimer level and DVT after ESD. Results: (1) 176 patients underwent vascular ultrasound examination of lower extremities 3 days after surgery, and 12 patients (6.82%) had lower extremity DVT. (2) There were statistical significance in D-dimer levels between the two groups before and 1 day after ESD (all P <0.05). (3) The sensitivity, specificity and AUC of D-dimer 1 day after ESD to predicted DVT were 91.7%, 67.1%, 0.841 (95% CI: 0.778-0.892). (4) Multivariate regression analysis showed that the level of D-dimer (Log) 1 day after ESD was significantly correlated with the increased risk of DVT after ESD (OR, 82.756; 95% CI, 6.000-1141.349; P <0.001). Conclusion: The increased level of D-dimer 1 day after ESD is associated with an increased risk of deep vein thrombosis in patients with early gastric cancer and premalignant lesions underwent ESD.